The 22 patients (13 women) had a median age of 69.5 years (range, 47-81 years). Twenty-one of the patients were non-Hispanic white, and 1 patient was black. Patients were residents of 16 different US states ().
Demographic Characteristics, Outcome, and Alternative Antihypertensive Drugs Used After Suspension of Olmesartan in 22 Patients With Spruelike Enteropathy
The most frequent clinical diagnoses at time of referral were nonresponsive/refractory celiac disease (n=10) and unexplained sprue (n=6). Most patients were taking 40 mg/d of olmesartan (range, 10-40 mg/d) for several months or years before the onset of diarrhea. Detailed information about the duration of exposure to olmesartan before onset of diarrhea was available in the medical record in 14 patients (64%). Among these, the mean duration was 3.1 years (range, 0.5-7 years). An additional 5 patients were taking olmesartan for at least 1 year before the onset of symptoms. Information about duration of exposure to olmesartan before onset of diarrhea was not available in 3 patients.
Diarrhea had been present for a median of 19.2 months (range, 3-53 months) before suspension of the drug. At the time of presentation, all patients had diarrhea and weight loss (median weight loss, 18 kg; range, 2.5-57 kg). Nausea and vomiting were present in 15 patients (68%), abdominal pain in 11 (50%), bloating in 9 (41%), and fatigue in 15 (68%). The onset of diarrhea was sudden in 9 patients. The stool frequency was extremely abnormal, with a median of 6 evacuations per day (range, 3-42 evacuations per day). Among 8 patients with timed stool collection, the mean stool weight was 933.1 g/24 h (range, 225-3225 g/24 h), and mean fecal fat was 28.3 g/24 h (range, 8-50 g/24 h). Although timed stool weight was not investigated in all patients, 14 patients (64%) required hospitalization because of severe dehydration (4 patients had acute renal failure). Total parenteral nutrition was necessary in 4 patients. At the time of the first visit at Mayo Clinic, 11 of the patients had normal weight, 6 were underweight, 4 were overweight, and 1 was obese. All but one patient (patient 16) met criteria for severe enteropathy.
Results of IgA tissue transglutaminase antibody testing were negative in all patients. IgA endomysial antibody results were negative in all 9 patients who underwent testing. HLA-DQ typing was performed in 21 patients: DQ2 was present in 15 patients, DQ8 in 2 patients, and neither DQ2 nor DQ8 in 4 patients. Anti-enterocyte antibody testing was done in 19 patients (86%), and results were negative in 16 (including 7 patients who had a positive nonspecific nuclear pattern of unknown clinical significance) and positive with a linear/apical pattern in 3.
Fourteen patients (64%) had normocytic normochromic anemia (2 had elevated red blood cell distribution width suggesting anisocytosis); the lowest hemoglobin level was 9.3 g/dL. Ten patients (45%) had hypoalbuminemia; the lowest albumin level was 2 g/dL. Twelve patients (55%) had one (n=3) or multiple (n=9) electrolyte abnormalities. Zinc deficiency was documented in 7 patients.
Small bowel bacterial overgrowth was confirmed by culture of duodenal aspirate (>105 colony-forming units per milliliter) in 12 patients at some point during clinical evolution. A trial of oral antibiotics was used in 10 patients without clinical benefit (rifaximin in 5, tetracycline in 3, ciprofloxacin in 1, and ciprofloxacin-metronidazole in 1). An additional 2 patients received no therapy for small bowel bacterial overgrowth.
In all patients, baseline intestinal biopsies demonstrated villous atrophy with variable degrees of mucosal inflammation (). Total villous atrophy was observed in 15 patients and partial villous atrophy in 7 patients. A thick band of subepithelial collagen deposition (collagenous sprue) was seen in 7 patients (2 cases had been reported previously5
). Active/acute inflammation was observed in 15 patients, and increased intraepithelial lymphocytes were found in 14 patients. Aberrant (or clonal) intraepithelial lymphocytes were not detected among the 12 patients tested.
Histologic Findings in 22 Patients With Spruelike Enteropathy Associated With Olmesartana
Colonoscopy with random colonic biopsies was performed in 13 patients (59%). Microscopic colitis was found in 5 patients (2 had lymphocytic colitis and 3 had collagenous colitis).
Biopsies of the stomach were available in 14 patients (64%). Lymphocytic gastritis was diagnosed in 5 patients and collagenous gastritis in 2 patients. Chronic gastritis was diagnosed in an additional 7 patients (1 had Helicobacter pylori infection).
Treatment and Subsequent Course
Most of the patients in our study had undergone several therapeutic trials, without apparent clinical benefit, before referral to Mayo Clinic, including the use of a gluten-free diet for months (n=20), systemic corticosteroids and/or budesonide (n=20), opioid-derived antidiarrheal agents (most often loperamide) (n=10), pancreatic enzymes (n=4), bile acid sequestrant (n=4), metronidazole (n=4), azathioprine (n=3), and octreotide (n=3).
Clinical response was observed in all 22 patients after suspension of olmesartan. Besides tapering of corticosteroids, no medication was needed to control diarrhea after clinical response was achieved with suspension of the drug. Patients following a gluten-free diet were advised to abandon the diet immediately if they lacked the celiac susceptibility genotypes or to gradually reintroduce gluten if they were HLA-DQ2 or DQ8 positive. No patient had recurrence of symptoms after restarting a gluten-containing diet. Follow-up body weight after suspension of olmesartan was available in 17 patients; 16 had weight gain, with a mean weight gain of 12.2 kg (range, 2.9-28 kg), and 1 patient (patient 5) who had edema at diagnosis lost 4.1 kg during follow-up despite clinical remission.
At the time of this report, follow-up intestinal biopsies have been performed in 18 patients (82%) after a mean of 242.3 days (range, 54-707 days) from the date of suspension of olmesartan. Histologic recovery of the duodenum was documented in 17 patients (). Focal partial villous atrophy was observed in 1 case (patient 2) on a follow-up duodenal biopsy obtained 54 days after suspension of olmesartan. Follow-up gastric biopsies were performed at the same time as repeated biopsy of the duodenum in 6 of the 7 patients with either lymphocytic or collagenous gastritis (no gastric biopsy results were available for patient 11). Follow-up gastric biopsies showed normal mucosa in 4 patients and nonspecific mild chronic gastritis in 2 patients (patients 20 and 22). Follow-up colonoscopies with biopsies of the colon were not performed in the 5 patients with microscopic colitis.
FIGURE Photomicrographs showing reversible spruelike enteropathy associated with olmesartan (hematoxylin-eosin, original magnification ×100). A, Duodenal biopsy specimen obtained while the patient was taking olmesartan shows total villous atrophy and (more ...)