Advances and challenges in diagnosing and managing adult autoimmune enteropathy

Abstract

Autoimmune enteropathy (AIE) is a rare immune mediated disorder primarily affecting children, characterized by chronic diarrhea, malabsorption, vomiting, weight loss and villous atrophy. It has also been observed in adults presenting diagnostic and treatment challenges due to its overlap with other gastrointestinal disorders such as celiac disease. Initial diagnostic criteria for AIE include small bowel villous atrophy, lack of response to dietary restrictions, presence of anti-enterocyte antibodies, and predisposition to autoimmunity without severe immunodeficiency. Refined criteria emphasize characteristic histological findings and exclusion of other causes of villous atrophy. AIE is associated with various autoimmune disorders and can present with overlapping features with Celiac disease, including villous atrophy but without significant intraepithelial lymphocytosis. Treatment primarily involves immunosuppression using corticosteroids, calcineurin inhibitors, and anti-tumor necrosis factor therapy, alongside nutritional support. Despite the challenges, understanding AIE’s diverse manifestations and improving diagnostic criteria are essential for effective management and improved patient outcome. Further research is needed to elucidate the pathogenesis, disease progression and long-term outcomes of AIE.

Key Words: Autoimmune enteropathy; Diagnosis; Prognosis; Adult autoimmune enteropathy and challenges; Autoimmune enteropathy and treatment; Autoimmune enteropathy and diagnostic criteria; Pathophysiology of autoimmune enteropathy

Core Tip: Autoimmune enteropathy (AIE) is a rare, immune-mediated disorder predominantly affecting children, characterized by chronic diarrhea, malabsorption, vomiting, weight loss, and villous atrophy. Adults can also be affected, complicating diagnosis and treatment due to symptom overlap with other gastrointestinal disorders. Key diagnostic criteria include small bowel villous atrophy, lack of response to dietary restrictions, presence of anti-enterocyte antibodies, and a predisposition to autoimmunity without severe immunodeficiency. Further research is needed to elucidate the pathogenesis, disease progression and long-term outcomes of AIE.

TO THE EDITOR

In this letter, we comment on the article published by Li et al[1]. Autoimmune enteropathy (AIE) is a rare immune-mediated disorder that primarily affects children, presenting with chronic diarrhea, malabsorption, vomiting, weight loss and villous atrophy[2,3]. This condition was identified by Unsworth and Walker Smith[2]. It is a rare immune intestinal disorder rarely observed in adults and is characterized by uncontrollable diarrhea leading to malabsorption[4]. Immune dysregulation, X-linked (IPEX) syndrome, enteropathy, polyendocrinopathy and mutations in FOXP3 which is a master gene of regulatory T cells, can lead to AIE. Recent study has demonstrated that mutations in other T cells associated genes, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and cluster of differentiation 25 (CD25), can result in an IPEX-like phenotype[5]. Genetic studies have identified several monogenic immune disorders that can present as AIED in adulthood. These include lipopolysaccharide responsive beige-like anchor protein deficiency, CTLA4 haploinsufficiency, and nuclear factor kappa B subunit 1 mutation, all of which have been linked to adult-onset AIE[6].

The initial prognosed diagnostic criteria for AIE also include lack of response to dietary restriction, small bowel villous atrophy, predisposition to autoimmunity and/or presence of anti-enterocyte antibodies, with no evidence of deficiency of the immune system, such as hypogammaglobulinemia or common variable disorders of the immune system leading to immunodeficiency. Updated criteria have been emphasizing specific histological findings such as abnormal apoptosis, villous blunting, minimal intraepithelial lymphocytosis, and, deep crypt lymphocytosis, along with the exclusion of different reasons of villous atrophy. The presence of gut-specific antibodies is no longer required for diagnosis[7].

Lymphocyte deposits are present on the mucous membrane, and most affected individuals have anti-enterocyte or anti-goblet cell antibodies. Immunosuppressive drugs have been used with varying degrees of success. The prognosis of AIE depends on the severity of the intestinal mucosal damage and any associated extraintestinal symptoms and diseases[8].

The diagnosis of AIE is based on a characteristic combination of clinical signs, laboratory findings and histological features seen in small intestine biopsies. AIE often occurs with many other conditions and syndromes, especially notably IPEX syndrome and autoimmune polyglandular syndrome type 1. Diagnosing and managing AIE remains complex, and further research is needed to understand its underlying mechanism, disease progression and outcomes that will occur in the future[9].

The clinicopathologic manifestations of AIE are linked to a diverse group of disorders. The exact mechanisms underlying the AIE are still not fully elucidated. It appears to result from disrupted immune regulation of intestinal immunity alongside immunodeficiency. The overarching histopathologic changes seen in AIE include mucosal inflammation and damage to the epithelial layer, although these can manifest in various patterns[10]. Although AIE affects the entire gastrointestinal tract, nearly all cases show altered duodenal histology that follows known patterns with or without visible changes[4].

Clinical manifestations-diagnosis and long-term prognosis

AIE is a rare disorder marked by an abnormal immune response in the intestines, typically manifesting as severe diarrhea within the 1^st 6 months of life. AIE is currently classified into five subcategories, the main AIE, syndromic (pediatric) AIE, primary (sporadic) AIE over 18-years-old, secondary (iatrogenic-driven) AIE in people over 18-years-old, and paraneoplastic AIE. Endoscopic findings in AIE can vary and include mucosal hyperemia, scalloping, ulcerations, and a mosaic appearance[7,11].

The underlying mechanisms of AIE are not completely understood, but evidence points to an overactive immune response caused by a defect in regulatory T-cell homeostasis[11,12]. It is a result from an imbalance in humoral and cellular immune function, driven by a defect in the regulatory T-cell system[2,12]. AIE has been incorporated in the IPEX syndromes (polyendocrinopathy, immunodysregulation, enteropathy X-linked) because it is frequently associated with other autoimmune disorders. For patients that have this condition, it is possible to have other autoantibodies, including liver/kidney microsomal antibodies, antinuclear antibodies, and anti-smooth muscle antibodies[12].

The following criteria exist to diagnose AIE such as the protracted diarrhea, failure to respond to an exclusion diet, absence of severe immunodeficiency and evidence of autoimmunity[13]. It has also been proposed as a morphological classification as it relates to duodenal mucosa, identifying four main histological patterns: (1) Active duodenitis; (2) Celiac disease (CD)-like pattern; (3) Acute graft versus host-like disease; and (4) Mixed pattern[11].

On the other hand, the adult AIE is defined by the following criteria such as the adult-onset protracted diarrhea (more than 6 weeks) that does not respond to any form of dietary exclusion. Also, the characterizing small-intestine histology, including villous atrophy, minimal intraepithelial lymphocytes with increased crypt apoptotic bodies, on absence of goblet or Paneth cells. Last but not least, the thorough elimination of other potential causes of villous atrophy, including CD or refractory CD, determined through combination of human leukocyte antigen (HLA) typing, celiac serology, histopathology features and response to a gluten free diet and enteropathy associated with common variable immunodeficiency determined by total immunoglobulin levels and histopathology[12,13].

Iaquinto et al[3] studied a case repost of a 73-year-old woman with a history of antinuclear antibodies, autoimmune hepatitis, and positive anti-enterocyte antibodies. She experienced 2 months of persistent diarrhea, nausea, loss of appetite and significant weight loss. Histological analysis of the duodenal mucosa showed severe villous shortening and flattening, leading to mucosal atrophy. An immunohistochemical study revealed a polymorphic lymphoid population, with B cells present in follicles and T cells in the diffuse component of the lamina propria. Remarkably, the patient had a complete recovery after 2 weeks of prednisolone treatment and following a gluten rich diet.

In another study, Chong et al[4] studied a case of seronegative AIE with atypical duodenal manifestations in a female (43-years-old). The diagnosis of AIE was confirmed by identifying mononuclear inflammation of the lamina propria, crypt epithelial apoptosis, and goblet cell loss in the intestinal mucosa beyond the duodenum. When colonic histological changes consistent with AIE are present, along with diarrhea and malnutrition despite sparing of the duodenum, it should raise suspicion for AIE due to the disease’s pan-enteric nature.

Clinicians should consider AIE in their differential diagnosis for patients diagnosed with CD who do not respond to a strict gluten free diet. Studies describe cases where patients with AIE have both positive gluten sensitivity antibodies and celiac-associated HLA markers. There is also documented overlap in small intestinal biopsy findings between AIE and CD patients. While villous atrophy is seen in both CD and AIE, AIE is characterized by the absence of significant intraepithelial lymphocytosis and mucosal injury in other locations outside the small bowel, including esophagus, stomach and colon. Additionally, AIE is well documented to be associated with other autoimmune diseases[2]. AIE and CD differ in terms of their demographics, clinical presentation and response to treatments. As regard to the patient demographics, the men are affected at a higher proportion (60%) with AIE compared to CD and the average age pf patients with AIE is younger. In CD patients, chronic diarrhea is less frequent (71%) than in AIE patients (100%)[11].

The treatment of AIE is challenging and primarily relies on immunosuppression. This includes the use of corticosteroids, calcineurin inhibitors, and anti-tumor necrosis factor therapy. Nutritional support is also a crucial component of the treatment regimen[12]. A study presents a case of AIE with severe diarrhea, leading to multiple hospitalizations and parenteral nutrition. This patient is successfully managed with Ustekinumab. This suggests that Ustekinumab warrants further investigation as a potential treatment option[14]. Another study showed that treatment with corticosteroid had a good response but required total parenteral nutrition during her stay in the hospital. That was studied in an 82-year-old woman with a history of autoimmune thyroiditis with significant weight loss and diarrhea[15]. The treatment involves immunosuppression to eliminate inflammation in the small intestine. Prednisolone and budesonide combined together, have been used with varying degrees of success. When these treatments are ineffective, potentially harmful agents such as adalimumab, infliximab, or tacrolimus are often considered, though their success rates can also vary. Long-term use of these agents may increase the risk of systemic adverse effects[13].

CONCLUSION

In conclusion, AIE is a rare and challenging condition to diagnose and treat due to its varied manifestations and overlap with other gastrointestinal disorders. Our case studies highlight the importance of considering AIE in patients with persistent gastrointestinal symptoms unresponsive to conventional treatments, even when typical histologic changes are absent in the duodenum. The identification of specific histological features, such as crypt epithelial apoptosis, mononuclear inflammation, and goblet cell loss in the intestinal mucosa beyond the duodenum, can be crucial for diagnosis. The effectiveness of immunosuppressive therapy, particularly with prednisolone and budesonide, underscores the potential for restoring immune equilibrium and achieving long-term remission. Continued research and awareness are essential for improving diagnosis, treatment and long-term outcomes.