Abstract

A 65-yr-old female with diarrhea for 3 months and weight loss was evaluated. There was no travel or family history, but she had been treated with olmesartan for an elevated blood pressure. Fecal studies for an infectious cause were negative and serological studies for celiac disease were negative. A small bowel biopsy showed changes of collagenous sprue. The drug was discontinued. Diarrhea ceased and she regained her weight. Repeat biopsies of the small bowel were normal. Except for cessation of the olmesartan, no other dietary (eg., gluten-free diet) or treatment medication (eg., steroids) was provided. Long-term follow-up revealed no recurrence of symptoms in patients with sprue-like intestinal disease or collagenous sprue, consideration should be given to a drug-induced cause. This may limit the need for further clinical studies, restrictive diets or powerful prescribed medications, including steroids and immunosuppressive agents.

1. Introduction

Collagenous sprue (enteritis) is a mucosal disorder of the small intestine characterized by a very distinct histopathological lesion first described over 50 years ago ^{1, 2, 3}. Severe and persistent diarrhea occurs accompanied by pan-malabsorption of multiple nutrients, protein wasting and profound weight loss. Initially, the disorder was believed to often be fatal but more recent reports have suggested that the disorder is heterogeneous and some patients may have a more positive outcome ^{4, 5}. In general, published treatments must be considered only anecdotal, largely because most physicians have only acquired a limited management experience, published series are limited to a few patients and no randomized clinical trials have been done.

The disorder was first labeled for its classical small intestinal mucosal biopsy appearance with a sub-epithelial band-like deposit showing histochemical and ultrastructural features of collagen ³ and extensively reviewed later ⁶. Other histopathological changes include a “flattened” villus architecture similar to untreated celiac disease that fails to respond to a gluten-free diet, so-called sprue-like intestinal disease. Occasionally, collagen deposition has been documented in other gastrointestinal sites, including gastric and colonic mucosa ⁶. In some, celiac disease was thought to be present but evaluation was later pursued because of “refractory” symptoms ³, while in others, the small bowel disease was never shown to respond to a gluten-free diet, important in definition of celiac disease, a gluten-dependent disorder. However, other clinical features in collagenous sprue shared with celiac disease have been noted: hyposplenism or splenic atrophy ⁷, small intestinal ulceration with free perforation ⁸, and T-cell lymphoma that may co-exist or complicate the clinical course of collagenous sprue ^{9, 10}.

Recently, another twist in this narrative on collagenous sprue has occurred. As in celiac disease, the histopathological changes are not specific and different causes have been recognized. For instance, drug toxicities are well recognized to cause sprue-like changes in small bowel biopsies ¹¹. In recent years, however, similar drug toxicity concerns have been raised in collagenous sprue. For instance, non-steroidal anti-inflammatory drugs were suspected to play a role in pathogenesis of collagenous sprue and colitis, in part, because these patients commonly have associated arthritic autoimmune disorders. Interestingly, celiac antibodies, including tissue transglutaminase antibodies, may be positive in some, but not all patients. Resolution of collagenous sprue after cessation of non-steroidal anti-inflammatory drugs has been reported ¹². The possible significance of other commonly prescribed medications for hypertension have also been noted, including drugs in the angiotensin II receptor antagonist class, particularly olmesartan ¹³.

2. Case Report

A 65 year old female developed worsening diarrhea up to 5-6 times per day over a 3 month period. During this time, weight loss, estimated to be almost 10 kg was noted. Bloodwork was normal, including a hemogram and iron studies. Antibodies to tissue transglutaminase were negative and serum immunoglobulins were normal. Fecal studies for bacterial and parasitic agents, including Clostridium difficile, were negative. A colonoscopy with biopsies was normal without findings of colitis or collagen deposits. Upper endoscopy appeared normal except for some non-specific changes including apparent thickening and scalloping of the duodenal mucosa (Figure 1 and Figure 2). Gastric biopsies were normal with no collagen deposits. Duodenal biopsies revealed changes of collagenous sprue (Figure 3).

The patient also reported that her prior health was normal, except for an elevated blood pressure recording initially self-obtained during a shopping visit in a local food market about a year earlier. This was confirmed by her own physician and she was treated with olmesartan 20 mg daily. A gluten-free diet was not administered. Cessation of drug led to complete resolution of diarrhea and weight gain. After a year, her biopsies were normal. Now, 3 years later, she had remained well and takes chlorthalidone alone for her hypertension.

3. Discussion

Olmesartan enteropathy has been described as a small intestinal sprue-like disease characterized by severe diarrhea, weight loss and pathologic features of untreated celiac disease. In some, the disease has required hospitalization. In the patient here, collagenous sprue was detected after her presentation with diarrhea and weight loss following treatment of her hypertension with olmesartan. There was no other history of intestinal disease, including celiac disease and she was not using other medications. Gastric and colon biopsies were normal.

Her symptoms and small intestinal biopsy changes resolved completely after cessation of olmesartan. No recurrence has occurred during long-term follow-up period over more than 3 years. Further re-evaluation and biopsy after re-introduction of olmesartan was not considered, since other alternatives were readily available to safely manage her elevated blood pressure.

Sprue-like enteropathy associated with olmesartan was previously reviewed ¹³. In some, differentiation from underlying celiac disease may difficult, especially if serologic screening studies (eg., tissue transglutaminase) are positive and no response to a gluten-free diet occurs. In the present seronegative patient here, collagenous sprue was defined and olmesartan simply stopped with resolution of her symptoms and normalization of her small intestinal biopsies. Similar histologic recovery or resolution was noted after cessation of the drug by others ^{14, 15, 16}, however, other forms of treatment were usually provided, including a gluten-free diet and, occasionally, steroids. In one of these reports, however, added evidence for a role of olmesartan was provided with challenge studies ¹⁶, not done in the present evaluation. In a similar report to the present case, the authors warned about the possibility of unnecessary exposure to high doses of steroids in this setting where sole cessation of olmesartan alone may be sufficient ¹⁶. There appears to be a wide range of clinical severity of this disorder and, consequently, it is likely to be under-recognized and under-reported.

References