The Spectrum of Autoimmune Enteropathy

Chronic, unexplained diarrhea in children younger than 3 months old was first characterized as “intractable diarrhea” [1]. The term “protracted diarrhea” was used later to describe infants with frequent and loose stools severe enough to often require parenteral alimentation as nutritional support [2]. The differential diagnosis of enteropathies in infancy and childhood includes inherited epithelial and congenital transport defects, enzymatic deficiencies and allergic enteropathy (Table 2.1). The most frequent diagnosis in children with protracted diarrhea is autoimmune enteropathy (AIE) [3, 4]. It is a rare, immune-mediated disorder starting usually within the first months of life. The age of onset is between 1 month and 5 years (median age 17 months) [5], but late-onset adult forms have been also reported [6–9]. The disease was first described by Walker-Smith et al. in 1982 in a male child with clinical features of coeliac disease and villous blunting unresponsive to gluten-free diet [10] and represents a heterogeneous group of disorders rather than a discrete entity. The incidence is estimated at less than 1 in 100,000 infants. The diagnostic criteria are debatable but the presence of circulating anti-enterocyte antibodies and the lack of immunodeficiency have been proposed as the hallmark features of AIE [5, 11]. The latter criterion has been challenged by clinical experience and better understanding of the immunology of autoimmunity and self-tolerance [12]. AIE is characterized by variable clinical expression, ranging from isolated gastrointestinal involvement to severe systemic disease [13, 14]. Patients diagnosed with the disease often exhibit extra-intestinal manifestations of autoimmunity, in contrast to those with tufting enteropathy and microvillus inclusion disease [15]. Based on a genetic approach combined with immunological evaluation, three different forms of AIE have been proposed: