Introduction
Autoimmune enteropathy (AIE) is a rare intestinal disease characterised by intractable diarrhoea and immune-mediated intestinal mucosal damage [
1]. The incidence of AIE is 0.06 out of 100,000 children; most cases are associated with growth retardation while some children have other comorbid autoimmune diseases [
2]. Clinical manifestations of AIE include intractable diarrhoea, severe nutrient malabsorption, and hypoproteinaemia. Small intestinal villus atrophy is a main histopathological feature, among other manifestations such as lymphocytic infiltration in the lamina propria of mucosa, chronic inflammation characterized by increased or active apoptotic bodies in the crypt epithelium, and neutrophilic cryptitis. Anti-intestinal epithelial (AE) or anti-goblet cell (AG) antibodies are present in the serum. In 1978, McCarth et al. [
3] reported a case of severe intestinal mucosal atrophy in a child and then proposed the concept of AIE. In 1997, based on the clinical data of 14 patients, the Mayo Clinic proposed the diagnostic criteria that are still in use today [
4]: (1) chronic diarrhoea (duration > 6 weeks); (2) manifestations of malabsorption syndrome; (3) manifestations of specific small bowel lesions: partial/complete villous atrophy, deep crypt lymphocytosis, increased crypt apoptosis, and increased intraepithelial lymphocytes; (4) exclusion of other causes of villous atrophy, such as Crohn’s disease, sprue, and small intestinal lymphoma; and (5) positivity for AE and/or AG antibodies. Among them, conditions (1)–(4) are necessary for the diagnosis of AlE. Positive AE or AG antibodies can support the diagnosis; however, an absence of positive antibodies cannot exclude the diagnosis of AIE.
Diagnosis of AIE is challenging, requires small bowel biopsy, and often confused with other caoditions causing glycogenic diarrhea, celiac disease, inflammation bowel disease, gene mutations related immune deficiency disease, and so on.
Given the rare nature of AIE, most articles on this disease have been isolated case reports or case series, lacking multi-centre statistical data, especially the clinical characteristics of children at different ages. Therefore, this article will further deepen our understanding of the disease by comparing the clinical characteristics of children of different ages at time of disease onset.
Results
Five children in our hospital received routine rehydration therapy, parenteral nutrition support, and diet restriction after admission; but diarrhoea symptoms were not relieved. Through further examinations to exclude inflammatory bowel disease, celiac disease, stomatitis diarrhoea, small intestinal lymphoma and other diseases that may cause atrophy of small intestinal villi, a whole exon gene examination was performed, and no mutation of pathogenic site was found, which met Mayo diagnostic criteria [
4], and the final diagnosis was AIE. Glucocorticoid therapy was administered at an initial dose of 2 mg/kg/day of methylprednisolone. Except for cases
4 and
5, the diarrhoea symptoms were relieved, whereas in other children, it was not immediately beneficial. After the dosage increased to 4 mg in cases
1–
3, the symptoms of loose stool in cases
2 and
3 were relieved. These symptoms reappeared in the process of glucocorticoid reduction to 4 mg/day but were relieved once tacrolimus was added to the treatment course. In case
1, the symptoms were relieved by treatment with glucocorticoid combined with cyclosporine, but the symptoms reappeared in the process of adding normal diet, and rescue treatment with infliximab was ineffective. After adjusting the immunosuppressant dose to include tacrolimus, clinical remission was achieved.
Clinical characteristics of five children in our hospital are shown in Tables
1 and
2, and
3. Of the five cases, two cases had onset within 1 year of age, the mean onset age was 1.59 years old and the average time from onset to final diagnosis was 2.4 years. All children had malnutrition, anaemia, and hypoproteinaemia and were responsive to glucocorticoid therapy. One case in which the drug was completely stopped, and the other three cases needed immune drugs to be maintained, there is also one patient with hormone reduction under observation.
Statistical analysis was performed on the clinical data of the 50 children (Table
4). The ratio of males to females was 31:19, with boys being more affected by AIE. The average age of onset was 1.6 years old, while 35 cases (70%) experienced onset within 1 year of age, among them 27 were onset within 6 months, and the average age of whom was 2.5 months. Clinical manifestations were mainly watery stools (43 cases, 86%), weight loss (28 cases, 56%), abdominal distension (3 cases, 6%), and positive erum AE or anti-goblet cell (AG) antibody (32 cases, 64%). Other immune-related antibodies were detected in 21 cases (42%): anti-thyroid antibody in 6 cases; anti-nuclear antibody in 10 cases; anti-insulin antibody in 2 cases; anti-Ergot antibody in 1 case; and anti-Saccharomyces cerevisiae antibody in 2 cases. Twenty-one children (42%) had combined family histories of AIE. All children had intestinal mucosal pathology showing different degrees of atrophy.
Gene mutations related disease were found in a total of 9 cases (18%): two cases immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX),three cases hypogammaglobulinemia, one case autoimmune polyendrocrinopathy-cadidiasis-ectodermal dystrophy (APECED), one case Kabuki syndrome, one case X-linked immunodeficiency, and one case hyper-IgE syndrome.
42 cases received drug treatment after diagnosis (Table
5), 7 cases of simple glucocorticoid, 18 cases of tacrolimus, 9 cases of azathioprine, 2 cases of cyclosporine, 2 cases of cyclophosphamide, and 4 cases of maintenance therapy with parenteral nutrition. Thirty-seven cases achieved clinical remission after drug treatment (74%), five cases died of infection after adding immunosuppressants, and eight cases died without medication.
The children in our study were divided into infant (≤ 1 year old) and child (> 1 year old) groups. The chi-square test was used for the analysis (Table
6). The mortality rate of children with onset in infancy was higher (P = 0.005, < 0.05). There was no significant difference in other autoimmune diseases, in the AE antibody-positive rate, and other antibodies between the two groups. In addition to age group, there was no difference in sex, autoantibody positivity rate, single gene mutation, or family history between the two groups through analysis of death and clinical remission case groups (Table
7).
Table 1
Clinical characteristics of 5 AIE patients of our hospital
1 | F | 2.2 | 4 | Watery stools, abdominal distension | -3.5 | N |
2 | F | 0.4 | 6 | Watery stools | -1.7 | N |
3 | M | 0.16 | 7 | Watery stools | -5.1 | N |
4 | F | 2 | 120 | Mushy stool, abdominal distension | -3.15 | N |
5 | M | 3.2 | 9 | Watery stools, abdominal distension | 0.3 | N |
Table 2
Laboratory examinations of 5 AIE children of our hospital
1 | 85 | 25 | P | N | Duodenal villi low and flat | Edema of terminal ileum mucosa | Not done | N | N | N |
2 | 78 | 29 | N | N | Duodenal mucosal oedema | Sparse villi in terminal ileum mucosa | Not done | fungal infection, cure | N | N |
3 | 68 | 25 | N | N | Low duodenal mucosa | N | Not done | N | Anti-thyroid antibody | N |
4 | 98 | 27 | N | N | Celiac-like changes in the descending duodenum | N | Lower and flat villi of upper small intestine | N | Anti-Saccharomyces cerevisiae antibody | N |
5 | 102 | 26 | N | N | Oedema in the duodenal bulb and descending part, along with sparse villi | N | The villi of the upper jejunum are low and flat | N | Anti-Saccharomyces cerevisiae antibody | N |
Table 3
Endoscopy, treatment and outcome of 5 AIE children of our hospital
1 | Villi low and flat | Duodenitis type | Glucocorticoid -Cyclosporin-Remicade-Tacrolimus | No diarrhea, weight gain | Tacrolimus maintenance |
2 | Villi low and flat | Duodenitis type | Glucocorticoid | Normal defecation and growth | No repetition after drug withdrawal |
3 | Villi low and flat | Celiac-like | Glucocorticoid - Tacrolimus | Defecate 1–2 times per day | Tacrolimus maintenance |
4 | Villi low and flat | Celiac-like | Glucocorticoid | Defecate 1 times per day, weight gain | Glucocorticoid reduction |
5 | Villi low and flat | Duodenitis type | Glucocorticoid - Tacrolimus | Defecate 1 times per day, normal weight | Tacrolimus maintenance |
Table 4
The clinical features of 50 AIE children
Sex |
M | 31(62%) |
F | 19(38%) |
Age(Y) | Average: 1.6y |
≤ 1Y | 35(70%) Average: 4.2 m |
<6 m | 27(54%) Average: 2.5 m |
≥6 m &≤1Y | 8(16%) Average: 10 m |
> 1Y | 15(30%) |
Clinical manifestation (Onset symptoms) |
Watery stools | 43(86%) |
Weight loss | 28(56%) |
Watery stools and weight loss at the same time | 27(54%) |
Abdominal distension | 3(6%) |
Vomit | 1(2%) |
Laboratory examination |
Positive AE antibody | 32(64%) |
Positive other antibodies | 21(42%) |
Gene mutations related disease | 9(18%) |
Mucosal atrophy | 50(100%) |
Positive family history | 21(42%) |
Table 5
The clinical therapeutic and outcome of 50 AIE children
Simple glucocorticoids | 7(14%) | Clinical remission |
Immune drugs | 31(62%) | 26 cases clinical remission(83%) |
Tacrolimus | 18 | 4 cases died, 14 cases Clinical remission(77%) |
Azathioprine | 9 | 1 case died, 8 cases Clinical remission(88%) |
Cyclosporine | 2 | Clinical remission |
Cyclophosphamide | 2 | Clinical remission |
Parenteral nutrition | 4(8%) | Partial remission of Intestinal symptoms, but no remission of growth retardation |
Table 6
The analysis of clinical features of the AIE patients from different ages
Age | N | P | N | P | N | P | Survival | Death |
≤ 1Y | 14 | 21 | 21 | 14 | 30 | 5 | 22 | 13 |
>1Y | 4 | 11 | 8 | 7 | 11 | 4 | 15 | 0 |
Chi-square | 0.834 | 0.192 | 1.034 | 11.126 |
P Value | 0.523 | 0.662 | 0.423 | 0.005 |
Table 7
The analysis of survival and outcome of the AIE patients from different ages
| F | M | N | P | N | P | N | P | N | P | N | P | N | P |
Relieve | 16 | 21 | 19 | 18 | 31 | 6 | 24 | 13 | 20 | 17 | 11 | 26 | 7 | 30 |
Death | 3 | 10 | 10 | 3 | 10 | 3 | 8 | 5 | 9 | 4 | 3 | 10 | 0 | 13 |
Chi-square | 1.746 | 2.718 | 0.294 | 0.046 | 0.932 | 0.217 | 4.603 |
P Value | 0.32 | 0.191 | 0.679 | 1 | 0.515 | 0.191 | 0.668 |
Discussion
Autoimmune enteropathy (AIE) is an autoimmune disease of unknown aetiology, characterised by villous atrophy of the small intestinal mucosal epithelium. Most of these cause chronic diarrhea and may be life-threating diarrhea in infancy.
The main clinical manifestation of AIE is severe and long-term secretory diarrhoea, which is characterised by a large amount of watery stools, with a diarrhoea volume of up to 5,000 mL/day. The effects of fasting and water deprivation are not typically beneficial and the faecal aetiology is negative. Parenteral nutrition is required to maintain water and electrolyte balance. Intestinal malabsorption can result in low body weight and poor growth [
18]. In addition, children with AIE are often prone to local and systemic infections related to the skin barrier, intestinal barrier, immunotherapy, and malnutrition [
19]. In this paper, five children who were clinically relieved by immunotherapy developed systemic infections and died. Endoscopic manifestations are mostly mild, with sparse or oedema of the small intestinal villi, and some of them show fan-shaped and fissure-like changes in the duodenum, which are difficult to distinguish from celiac disease. AIE can be isolated in the gastrointestinal tract or may be part of a systemic disease. In children, these systemic diseases are mostly primary immunodeficiency diseases that are mostly related to gene mutations [
5,
20]. Common diseases include immune disorders, multiple endocrine diseases, enteropathy, autologous multiple endocrine diseases, candidiasis, ectodermal dystrophy syndrome, and others [
21].
Laboratory tests for AIE lack specificity, and AE and/or AG antibodies are only present in the serum intestinal autoantibodies of some children. Positive serum AE or AG antibodies increase the possibility of AIE diagnosis, but is not necessary for diagnosis [
22]. It has been reported that serum intestinal autoantibodies appear only after the onset of mucosal injury and decrease or become negative with treatment before histological remission [
23]. Although many experts currently recommend their use as diagnostic criteria for AIE, the retrospective analysis in this paper shows that the positive rate of antibodies is only 64%. The presence of antibodies cannot be detected in all patients with typical AIE and not in other diseases either, such as inflammatory enteropathy, celiac disease, and HIV [
23‐
26]. In addition, peripheral blood autoantibodies that can be detected in AIE patients include anti-thyroglobulin, anti-thyroid peroxidase, and anti-Saccharomyces cerevisiae antibodies; however, their significance and diagnostic value in the pathogenesis of AIE are still unclear [
27]. Our retrospective statistical analysis also concluded that there was no difference between the presence of autoantibodies and remission rate and prognosis of treatment.
AIE has no specific histological features; however, all patients have gastrointestinal mucosal injuries. Injury is usually confined to the mucosa, while deep ulcers or transmural inflammatory changes are rarely observed. The pathological diagnostic criteria of AIE in the past were blunt villi, lymphocytosis in the deep crypt, increased apoptosis of crypt cells, and increased lymphocytes in the surface intraepithelium; however, at present, the pathological tissues of AIE can be divided into four types: active duodenitis (characterised by active chronic inflammatory process and neutrophil cryptitis, but without abscess), celiac disease-like, graft-versus-host disease-like (obvious apoptosis can be seen in crypts), and mixed mode. At present, all four types have been reported in paediatric patients [
5,
20,
28]. A retrospective study of the mucosal pathology of AIE showed that among 23 children, there were 10 celiac-like (43.3%), eight mixed mode, one acute GVHD mode, and four duodenitis modes, while for patients with immunodeficiency, the prevalence of celiac-like mode could be as high as 72% [
6]. Two of the confirmed cases in our hospital also showed a celiac-like pattern; therefore, this pattern is still very common among children, which is important in early differentiation and diagnosis.
These results suggest that the prognosis of patients with AIE depends on the severity of symptoms and signs of the digestive system, the severity and extent of histological lesions of the gastrointestinal tract, and the existence of parenteral involvement [
27,
29]. However, through retrospective analysis of case data, it was found that only the age of onset was closely related to mortality (Table
2), whereas there was no difference in family history, signs, or other diseases between the age groups. This may also be due to the fact that the number of cases we collected was mostly from the literature, and the purpose of case studies in the literature is specific and the description of pathological changes is different, which has a certain impact.
At present, there is no consensus on the treatment of AIE, because children with AIE often suffer from stunting due to nutritional absorption disorder, and their developmental conditions such as weight and height are mostly lower than those of normal children of the same age. The use of immunosuppressants based on nutritional support is recommended [
21,
23]. At present, there is no evidence-based treatment scheme owing to the lack of a large-scale sample and controlled trial evaluation. Glucocorticoids are the first choice for immunosuppressive therapy; when glucocorticoids are ineffective, tacrolimus, cyclosporine, tumour necrosis factor α monoclonal antibody, and other second-line treatment schemes can be selected for immunosuppressive therapy. Tacrolimus has been reported to have a high clinical remission rate (approximately 77%) for steroid-ineffective or refractory autoimmune bowel disease [
23], which is similar to the remission rate of the cases we collected (78%). All cases in this study were treated with hormone and immunosuppressive therapy, and most of them had clinical remission. A few children died of septicaemia, but the mortality rate was significantly lower than that of the untreated children. Therefore, early drug treatment can save the lives of children with AIE.
Overall, the clinical and histopathological manifestations of AIE in children, especially in infants, are quite varied. Early diagnosis and medication can reduce mortality and improve growth and development. Therefore, it is helpful for clinicians and pathologists to identify the clinical characteristics and different pathological patterns of AIE in its early stages.
This paper has limitations. Since the clinical data of 45 children were reported in the previous literature, the clinical remission time and follow-up after drug addiction were not fixed, so the overall evaluation and long-term clinical remission rate of drug treatment were uncertain. Therefore, the follow-up will strengthen the follow-up work of the confirmed patients in our hospital and help to evaluate the medication and clinical prognosis.
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