Olmesartan-induced enteropathy

Abstract

Olmesartan-induced enteropathy (OIE) typically presents with a constellation of signs and symptoms including chronic diarrhoea, weight loss and villous atrophy on biopsy. We describe a 68-year-old Caucasian woman with a history of hypothyroidism and hypertension who presented to our hospital with recurrent episodes of acute intermittent diarrhoea, nausea, vomiting, renal failure and 15 lbs weight loss. After an extensive workup, she was diagnosed with possible OIE. Cessation of the offending drug resulted in improvement of clinical symptoms and also hospital admissions for severe diarrhoea reinforcing the diagnosis of OIE. Among the adverse effects of drug therapy, diarrhoea is a relatively frequent adverse event accounting for about 7%. This report serves as an addition to existing literature and to increase the awareness of olmesartan-induced sprue-like enteropathy among the primary care physicians and gastroenterologists.

Background

Among the class of several angiotensin II receptor blockers used for hypertension, olmesartan was recently associated with severe sprue-like enteropathy.¹ It was approved for use as an antihypertensive medication in 2002.² Diarrhoea is the most common side effect of medications, although pathophysiology remains unclear in most cases. An association between the use of olmesartan and the development of unexplained severe enteropathy was first reported by Rubio-Tapia et al in 2012.¹ After the reported adverse effect by Rubio-Tapia et al, Mene and Haller analysed data from Randomised Olmesartan and Diabetes Microalbuminuria Prevention study database and did not identify a link between olmesartan use and the occurrence of enteropathy.³ Later, DeGaetani et al published a case series of 72 patients with villous atrophy and seronegative coeliac disease in May 2013.⁴ The US Food and Drug Administration issued a postmarketing adverse event warning in July 2013 to increase the awareness of clinicians about the sprue-like enteropathy associated with olmesartan.

Case presentation

A 68-year-old woman with a history of hypertension and hypothyroidism presented to the hospital with nausea, vomiting, non-bloody, non-mucoid, watery diarrhoea, intermittent abdominal pain for 2 weeks on June 2017. She denied using any recent antibiotics, travel and sick contacts. She also denied any tenesmus, melena, haematochezia and faecal incontinence. Her medications history included olmesartan 40 mg since 2009, levothyroxine 75 mcg and vitamin supplements. She was allergic to sulfa medications.

On admission, she was afebrile, heart rate 97 bpm, blood pressure 115/74 mm of Hg, respiratory rate 18/min and saturating 96% on room air. Physical examination was unremarkable except for dehydration. She was diagnosed with acute gastroenteritis and managed symptomatically with intravenous fluids, antiemetics, antibiotics and discharged home. During her follow-up with the primary care doctor, she resumed all her medications which were held during hospitalisation including olmesartan. One week after restarting the olmesartan, she presented to the hospital with severe diarrhoea-causing acute kidney injury on July 2017.

Investigations

Laboratory examination during the first episode revealed white cell count 5.380 ×10 ⁹ Cells/L, haemoglobin 14.7 g/dL, platelets 291 ×10 ⁹ Cells/L cells/dL, sodium 136 meq/L, potassium 3.8 meq/L, chloride 104 meq/L, bicarbonate 16 meq/L, blood urea nitrogen 45 mg/dL, and creatinine 4.3 mg/dL. Stool culture, Clostridium difficile, stool leucocytes and ova/parasites were negative. CT of the abdomen showed findings of colitis in right and transverse colon. She further underwent colonoscopy which showed findings of pan colitis and Ileitis with very flat to no villi. Biopsy also favoured acute infectious-type colitis as the cause. Retrospectively, she also had an episode of acute diarrhoea in late 2016 which she felt was turmeric related. She later had a screening colonoscopy in 12/2016 which was entirely benign including random biopsies. Previous normal colonoscopy strongly argues against a chronic colitis process. Thyroid stimulating hormone (TSH), free thyroxine level, erythrocyte sedimentation rate and C-reactive protein were normal. HIV testing was negative as well.

In July 2017, after the second episode of acute diarrhoea, she discontinued olmesartan, oesophagogastroduodenoscopy (EGD) and duodenal biopsies soon after revealed partial villous blunting, chronic lamina propria inflammation and subsurface collagen deposition with the detachment of overlying surface epithelium (figures 1 and 2). Other microscopic findings described in the literature which are associated with olmesartan-associated enteropathy varied from villous architectural distortion, increased intraepithelial lymphocytes, subepithelial collagen thickening, crypt apoptosis and crypt hyperplasia to lamina propria chronic inflammation with increased eosinophils. Antibody testing with tissue transglutaminase (tTG) immunoglobulin (Ig)A antibody, plus an IgA antibody was normal.

Figure 1.

Partial villous blunting, chronic lamina propria inflammation and subsurface collagen deposition with detachment of overlying surface epithelium.

Figure 2.

Partial villous blunting, chronic lamina propria inflammation and subsurface collagen deposition with detachment of overlying surface epithelium.

Olmesartan-induced sprue-like enteropathy is a possible diagnosis although a typical presentation would have been chronic non-bloody diarrhoea and weight loss.^{1 5} In the case series described by Rubio-Tapia et al, the onset of diarrhoea was sudden in nine patients.¹ Based on the cases reported until, olmesartan-induced enteropathy (OIE) has an equal predilection to male and female, with 68 years as the mean age of presentation. The average duration of exposure to olmesartan was 3.1 years (range 0.5–7 years).¹ Considering the duration of exposure to olmesartan, age, biopsy findings, negative workup for acute infectious, inflammatory, ischaemic colitis and malignancy, we diagnosed this case as olmesartan-induced diarrhoea.

Differential diagnosis

Seronegative intestinal villous atrophy and inflammatory infiltrates presents a diagnostic dilemma. The differential includes autoimmune enteropathy, coeliac sprue, graft versus host disease, common variable immune deficiency, small intestinal bacterial overgrowth and drug induced. However, graft versus host disease does not apply as our patient did not have any prior history of transplant.

Treatment

She was switched to the alternative antihypertensive drug, amlodipine. No further deliberate rechallenge test with olmesartan was undertaken due to the suspected morbidity associated with it.

Outcome and follow-up

Over the past 5 months after suspension of drug, clinical remission was achieved. She was given an option of repeating EGD and duodenal biopsies to see if inflammatory changes have resolved, but the patient feels well and is not inclined to have invasive testing at this time.

Discussion

We first suspected the possible connection between enteropathy and olmesartan when the patient asked if the disease process could be related to her antihypertensive drug. The unexplained clinical recovery during hospitalisation and prompt relapse following hospital discharge suggest that the association is not likely to be due to chance. We acquiesce that this case report lacks all the information required to prove causality but rather reflects an association.

The criteria for the diagnosis of severe enteropathy was defined by the presence of at least one of the following: (1) severe dehydration, electrolyte imbalance and/or acute renal failure requiring hospitalisation; (2) need for total parenteral nutrition and (3) weight loss of more than 10 kg. Rubio-Tapia et al described the clinical features of sprue-like enteropathy associated with olmesartan as following: (1) chronic diarrhoea, weight loss, steatorrhoea; (2) negative endomysial and tTG IgA antibody; (3) histopathological evidence of villous atrophy with or without collagen deposition or intraepithelial lymphocytosis; (4) no response to gluten-free diet; (5) exclusion of other causes of enteropathy and (6) clinical and histological evidence of improvement after discontinuation of the offending drug.¹

The mechanisms underlying olmesartan-induced sprue-like enteropathy are unexplained. The long quiescent period between onset of olmesartan and development of enteropathy is suggestive of cell-mediated immunity. Other proposed mechanisms are olmesartan-induced inhibition of transforming growth factor beta, an important mediator of gut homeostasis ⁶ and apoptosis of enterocytes due to disproportionate activation of type 2 angiotensin II (AT₂) receptors after blockage of AT₁.⁵ Rubio-Tapia et al also observed a higher prevalence of HLA-DQ2 in patients with OIE which may be associated with increased risk of developing this condition. A national survey conducted by Marthey et al reported 36 cases of OIE and one case of irbesartan-induced enteropathy which opens a new horizon to investigate other drugs of the same class.⁷

In a patient presenting with diarrhoea, the medical history is very important, especially the drug history, as it can suggest a diagnosis of drug-induced diarrhoea and thereby avoiding multiple clinical tests. Drug-induced diarrhoea is sometimes unrecognised or only diagnosed after a delay. The most frequent drugs which are involved in drug-induced diarrhoea are broad-spectrum antibiotics, laxatives, magnesium or calcium-based antacids, chemotherapy agents (azathioprine and mycophenolate)^{8 9} and colchicine. Proton pump inhibitors, non-steroidal anti-inflammatory drugs and ACE inhibitors are also implicated in causing diarrhoea, but less commonly.

We report a case to support a novel association between severe sprue-like enteropathy and olmesartan. Physicians who encounter patients with diarrhoeal syndromes should consider medications as a cause.

Learning points.

• Among the adverse effects of drug therapy, diarrhoea is a relatively frequent adverse event accounting for about 7%.

• In patients presenting with diarrhoea, a thorough medical and the drug history is of high importance, as it can suggest a diagnosis of drug-induced diarrhoea. Thereby, avoid multiple clinical tests.

• Differential diagnosis of olmesartan-induced enteropathy includes autoimmune enteropathy, coeliac sprue, graft versus host disease, common variable immune deficiency and bacterial overgrowth.

• Olmesartan-induced enteropathy is a rare cause of severe enteropathy that should be considered as a differential in patients presenting with chronic diarrhoea and who are taking olmesartan containing medications.