Identification of new cases of severe enteropathy has recently increased the spectrum of intestinal non-celiac villous atrophy

Abstract

From olmesartan-induced enteropathy to small CD4⁺ T-cell intestinal lymphoproliferation, the spectrum of non-celiac villous atrophy has recently been largely extended. Precise characterization of the different types of non-celiac enteropathy with villous atrophy is necessary to avoid misdiagnosis, to identify a causal mechanism and propound appropriate therapeutic strategies. This paper discusses how to use the different diagnostic tools to address diagnostic criteria, citing the examples of recent new cases of non-celiac enteropathy with intestinal villous atrophy.

Keywords:

• autoimmune enteropathy
• celiac disease
• intestinal lymphoproliferation
• olmesartan enteropathy
• villous atrophy

Within the past 20 years, the spectrum of non-celiac enteropathy with villous atrophy has considerably increased. Besides Whipple disease and tropical sprue [1], some entities have been more recently characterized such as adult autoimmune enteropathy [2], or common variable immunodeficiency (CVID) [3]. Expert histopathological analysis with immunohistochemistry is necessary for diagnosis of the precise type of intestinal non-celiac villous atrophy. For example, chorionic plasmocytic rarefaction and nodular lymphoid hyperplasia point out to CVID enteropathy, and the diagnosis can be confirmed by serum protein electrophoresis and anamnesis of frequent upper respiratory tract infections [3]. HLA of type II may also be useful as absence of HLA haplotypes encoding HLA-DQ2 or DQ8 excludes celiac disease as a cause of villous atrophy [4]. Nevertheless, genotypes HLA-DQ2/DQ8 can be found in non-celiac enteropathy such as in patients with CVID bearing celiac susceptibility genotypes in 77% of cases [3]. In situ studies of intestinal biopsy can be usefully completed by flow cytometric analysis of intestinal lymphocytes and multiplex PCR detection of T-cell rearrangements [5]. For example, CD4 lymphoproliferations are often misdiagnosed by routine histology and confused with clonal refractory celiac disease due to the combined presence of villous atrophy, decreased frequency of CD8⁺ intraepithelial lymphocytes (IEL) and presence of intestinal clonal T-cell receptor rearrangement [6,7]. Flow cytometry is very useful to demonstrate that, in contrast with type II refractory celiac disease, counts of CD103⁺CD3^– IEL are very low, while the frequency of CD103^–CD4⁺ IEL is increased due to diffusion of malignant lamina propria CD4⁺ T cells into the epithelial compartment. Flow cytometric determination of malignant CD4⁺ T cells is less informative in lamina propria that is naturally rich in CD4⁺ T cells but cytometry may allow identification of the T-cell receptor Vbeta chain used by the clonal malignant CD4⁺ T cells. Detection of this Vbeta chain is then helpful to monitor diffusion and response to treatment [6,7]. Serology is another complementary diagnostic tool. Anti-transglutaminase antibodies can be observed in one-third (5/15) of patients with adult autoimmune enteropathy and thus lack specificity to eliminate celiac disease [2]. In contrast, the presence of serum antibodies against enterocytes or goblet cells is characteristic of autoimmune enteropathy [2]. Serum antibodies can be detected by staining intestinal tissue sections and/or by radioimmunoassay detecting reactivity of anti-enterocyte antibodies reacting with the brush border 75-kDa antigen (AIE-75KD) first described in immune dysregulation, polyendocrinopathy, enteropathy and X-linked (IPEX) syndrome [8]. Several rare genetic immune diseases of Mendelian inheritance have recently been identified as a possible cause of autoimmune enteropathy. Most have an early onset in infancy. Yet, some such as cytotoxic T-lymphocyte-associated protein 4 haploinsufficiency and signal transducers and activators of transcription 3 activating mutations can be of incomplete penetrance and develop only at the adult age stressing the need to consider immunological workup and genetic analyses in these patients [9].

Pharmacological drugs such as mycophenolate mofetil may also cause intestinal villous atrophy [10]. The mechanism of its toxicity remains unclear. Recently, a new cause of sprue-like enteropathy has been described in association with use of olmesartan, an angiotensin II receptor antagonist used to treat arterial hypertension. Indeed, several cases of chronic diarrhea with weight loss, anemia and low serum albuminemia have been reported after the use of olmesartan [11]. In 2012, Rubio-Tapia et al. reported 22 cases of severe sprue-like enteropathy associated with olmesartan [12]. All patients displayed villous atrophy. Celiac susceptibility genotype HLA-DQ2 was found in around 68% of them, but no serum anti-transglutaminase antibodies were detected and none of the patients responded to a gluten-free diet. Notably, three of them had detectable serum anti-enterocyte antibodies. In another series of 72 patients with unexplained intestinal villous atrophy and negative celiac serology, 16 cases were ascribed to the use of olmesartan [13]. More recently, a French National cohort study reported 36 cases of olmesartan-induced enteropathy, 32/36 of which had villous atrophy but none of them had serum anti-transglutaminase antibodies [14]. In our experience (personal data) [15], olmesartan enteropathy can mimic autoimmune enteropathy. Common histological features were severe villous atrophy with glandular apoptotic lesions. One-third of patients displayed serum anti-AIE-75KD antibodies and, before olmesartan discontinuation, all had responded to immunosuppressive drugs [15]. A recent US study demonstrates that this severe gastrointestinal disorder is in fact a very rare adverse effect of this angiotensin receptor-blocker [16]. It is therefore possible that olmesartan enteropathy only affects predisposed individuals. The pathogenesis of olmesartan-induced enteropathy remains to be elucidated. Since angiotensin receptor blockers can inhibit signals from transforming growth factor beta, a key immunoregulatory cytokine [17], Rubio-Tapia et al. have suggested an immune-mediated mechanism. This hypothesis is supported by the increased prevalence of the HLA-DQ2/DQ8 genotype [12,15], the presence of extra-intestinal autoimmune diseases in one-third of our patients and the beneficial effect of immunosuppressive drugs, which sometimes need to be pursued several weeks after olmesartan discontinuation [15].

In conclusion, the use of new diagnostic tools has recently considerably extended the spectrum of non-celiac villous atrophy. Precise characterization of the enteropathy is indispensable to identify the causal mechanism and to propose a pertinent treatment.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.