September 2018 Case
Joseph S. Frye, MD (Resident), Deepti Dhall, MD (Faculty)
A 13 year old male with a history of Type 1 diabetes and persistent eczematous rash presented with chronic intractable watery diarrhea and failure to thrive. GI endoscopy revealed a mildly atrophic duodenal and ileal mucosa. The stomach and colon were unremarkable.
The duodenal and ileal mucosa showed marked to severe villous blunting, increased lamina propria inflammatory cells predominately lymphoplasmacytic with scattered eosinophils and neutrophils, foci of acute cryptitis, crypt abscesses and crypt apoptosis. Notably, there was marked decrease in goblet cells and Paneth cells (Figure 1, Figure 2 and Figure 3).
Biopsies from the stomach and colon were unremarkable.
CMV immunohistochemistry - Negative
Histologic findings consistent with Autoimmune enteropathy
Autoimmune enteropathies (AIE) are rare disorders that present as severe diarrhea during infancy or toddlerhood, however rarer cases have presented in adulthood. Typically they have small intestinal villous atrophy, not due to dietary (e.g. gluten-sensitive enteropathy or nontropical sprue) causes and have evidence of autoimmunity.
AIE traditionally involves the small intestine but may also involve other segments of the tubular gastrointestinal tract, like the colon and stomach. Histologically, sections of small intestine show severe villous blunting, mixed lamina propria infiltrate, crypt epithelial apoptosis, and lack of goblet/paneth/endocrine cells; as was seen in our case. In one series that reviewed 25 cases of AIE, they found that one of the most common patterns of injury on small intestinal biopsies is active chronic enteritis with prominent neutrophilic inflammation. However, this feature was only observed in 50% of cases.
It's important to recognize that some of these changes, like crypt apoptosis and blunting are not specific and may also be seen in acute Graft-versus-Host Disease and celiac disease. One of the diagnostic challenges is Celiac disease because it has overlapping histopathologic findings. As such serological studies for celiac disease should be ordered when villus blunting and mononuclear lamina propria expansion are the predominate findings. Even still, rare cases of AIE with positive celiac serologies have been reported and in such cases, the presence of other histological features of AIE (prominent apoptosis and absence of epithelial cell subtypes) may facilitate recognition of AIE. In the cases of overlapping AIE features with Graft-versus-Host disease, a good clinical history will help in differentiating the two entities.
The pathogenesis of AIE appears to be the consequence of immune dysregulation. Several genotypephenotype relationships have emerged, but two of the most well studied syndromes associated with AIE are: Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome and autoimmune polyendocrinopathy, mucocutaneous candidiasis, and ectodermal dystrophy (APECED) syndrome.
The underlying genetic mutations result in T cell over activity in these syndromes. In IPEX, mutations in FOXP3 lead to defective gut humoral and immune function. More specifically, loss of FOXP3 leads to immune over activity in response to antigen stimulation and cellular injury via CD4+ T cells. Mutations in the AIRE gene are associated with APECED syndrome. The AIRE gene plays a role in lymphocyte maturation and selection. When mutations occur, abnormal autoreactive T cells are allowed to expand and induce autoimmunity.
In our case, the patient had a clinical history that correlated well with the histopathologic findings. Given the age of onset, gender, and multisystem involvement IPEX was favored in this particular case. At the time of writing this discussion, no genetic analysis (i.e. FOXP3) had been performed. Additionally, repeat biopsies were not performed. However, it is well documented that histologic resolution of AIE occurs and improvement of symptoms may be seen with therapy. Treatment therapies vary but typically include steroids (i.e. prednisone), immune modulators (i.e. azathioprine, methotrexate) or anti-T-cell agents (i.e. tacrolimus).
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