Autoimmune Disorders of the Gastrointestinal Tract

Clinical Features

The clinical hallmark of AIE is refractory diarrhea, which may be accompanied by malabsorption and weight loss. In infants, low body weight and slow growth may be seen. The disease affects men and women within a broad age range. In the largest series of adult AIE cases reported, most patients were white, both sexes were equally affected, and the median age at diagnosis was 55 years.

This is an uncommon disease in adults, and most patients are initially misdiagnosed with celiac disease. A history of autoimmune disease is obtained in up to 87% of patients. Associated autoimmune conditions include hypothyroidism, rheumatoid arthritis, myasthenia gravis, idiopathic thrombocytopenic purpura, autoimmune gastritis, and polyneuropathy. Another notable association, particularly in children, is the relationship with other immunodeficiency syndromes. Three cases have been associated with thymoma. ^,

Because of the association of AIE with other autoimmune diseases, serological testing for autoantibodies is commonly positive. ^{, , ,} Autoantibody testing was positive in up to 67% of patients in one series. The antibodies, which are directed against a variety of antigens in patients’ sera, include ANA, anti-LKM, anti-SMA, anti-parietal cell, and many others ( Box 6.3 ). The relevance of gut epithelial cell antibodies is discussed later.

Other laboratory findings include normal B-lymphocyte and T-lymphocyte counts and complement levels. Some patients may have immunoglobulin A (IgA) deficiency, ^, but a broader immunoglobulin deficiency, especially if the albumin level is relatively normal, suggests common variable immunodeficiency (CVID), which can cause an enteropathy similar to celiac disease or AIE.

The small-intestinal endoscopic features, which include duodenal scalloping, erythema, erosions/ulcerations, fissuring, and a mosaic pattern, are generally nonspecific. ^, Similarly, there may be endoscopic abnormalities of the colon, including loss of vascular pattern, mucosal friability, contact bleeding, erythema, and ulceration. ^, Severe macroscopic colitis (including pancolitis) has been reported in patients with IPEX syndrome. There may be signs and symptoms of extraintestinal involvement. Abdominal CT may reveal mesenteric lymphadenopathy. ^,

Serological detection of antibodies directed against the intestinal brush border, and/or detection of cytoplasm of enterocytes and goblet cells, has constituted the mainstay of serological testing for autoimmune enteropathy. In their original series, Unsworth and Walker-Smith reported antienterocyte antibodies in 5 of 6 patients, and antienterocyte antibodies were detected in all 14 patients reported in two overlapping British series. ^, Antienterocyte antibodies are identified in 50% to 80% of patients, ^{, ,} and anti–goblet cell antibodies are seen in approximately 30% of patients. However, although these tests aid in the diagnosis of AIE, it has been argued, often persuasively, that these antibodies should not be included as diagnostic criteria for AIE because their direct role in epithelial injury has not been documented. Of greater concern, however, is that these antibodies are not specific (as mentioned earlier) or entirely sensitive for AIE. Antienterocyte antibodies have been noted in HIV infection, and anti–goblet cell antibodies can be detected in patients with IBD, celiac disease, ^, autoimmune hepatitis, chronic hepatitis C virus (HCV) infection, insulin-dependent and non–insulin-dependent diabetes, and in healthy controls. ^{, , ,} The presence of these antibodies may merely reflect epitope spreading and thus represent an epiphenomenon related to destruction of intestinal absorptive and goblet cells. Furthermore, there is no apparent correlation between antibody titer and histological severity.

As a practical matter, the presence of antienterocyte and anti–goblet cell antibodies should only be evaluated in conjunction with the clinical information and the histological findings. Their absence should not necessarily exclude the diagnosis of AIE.

Pathogenesis

Although the precise molecular mechanisms underlying AIE remain unknown, the robust relationship with other immunodeficiency disorders alludes to an alteration of gut immunity as the main mechanism behind this disorder. The intestinal mucosa is a site of complex interactions between the immune system and the environment, including dietary antigens and gut microflora.

The expression of HLA class II molecules, a key component of T-cell activation, is usually restricted to cells of the immune system, where they mediate antigen presentation and induction of the immune response. Although epithelial cells generally do not express HLA class II molecules, mature enterocytes at the tips of small-intestinal villi are an exception in that they constitutively express these molecules under normal physiological conditions and present antigens to autologous CD4+ helper T cells. Antigen presentation by enterocytes could, theoretically, suppress T-cell activity, which presumably allows for tolerance to dietary antigens encountered by small-intestinal epithelium, a phenomenon referred to as oral tolerance .

In contrast, enterocytes of AIE patients exhibit aberrant expression of HLA class II molecules, with inappropriate expression of HLA-DR in crypt enterocytes. ^, It has been hypothesized that aberrant HLA class II expression by crypt enterocytes induces CD4+ T-cell overactivity and subsequent T-cell–mediated injury of the intestinal epithelium through direct cytotoxicity or cytokine secretion. ^{, ,} Increased numbers of CD25+ T cells have been documented in small-intestinal biopsies of AIE patients, ^{, ,} and CD25+ T cells regressed with therapy in at least one case. Enterocyte injury by overactive T cells is emerging as a possible unifying mechanism to explain AIE.

Pathological Features

The small intestine appears to be the primary organ involved in AIE and the focus of most histological descriptions. However, it is becoming increasingly clear that the disease is rarely restricted to the small bowel because involvement of the stomach and colon are also commonly reported.

Small Intestine

The pathological features of AIE vary, but some patterns of injury may be considered characteristic, particularly in the duodenum, ileum, and jejunum. ^{, , , ,} Small-intestinal AIE can be largely grouped into three general histological patterns: (1) chronic active enteritis, (2) celiac disease–like pattern, and (3) graft-versus-host disease (GVHD)-like pattern. Biopsies that show multiple histological patterns are not uncommon. Although these patterns do not correlate with a specific disease phenotype, they are conceptually useful for the pathologist in generating a differential diagnosis.

The chronic active enteritis pattern is the most common pattern of injury. It consists of a lymphoplasmacytic inflammatory infiltrate with moderate to severe villous blunting and crypt hyperplasia ( Fig. 6.1 ). Neutrophilic inflammation may be prominent and sometimes occurs with crypt abscesses. Apoptosis may be present. Surface erosions and gastric foveolar metaplasia may be present. Eosinophils are typically seen but are not prominent.

The celiac disease pattern features increased intraepithelial lymphocytes, and villous blunting, and may be histologically indistinguishable from celiac disease ( Fig. 6.2 ). The GVHD pattern features increased apoptosis in crypt epithelium with a relative absence of inflammation, similar to acute GVHD. Apoptosis may be a striking feature in terms of the number of cells affected, and partial or total glandular destruction may be present. Other nonspecific reactive or regenerative epithelial changes include mucin depletion, crypt architectural irregularity, and increased mitotic activity.

In addition to the findings noted earlier, small-bowel biopsies may also show loss of multiple cell lineages, including goblet cells, endocrine cells, and Paneth cells (see Fig. 6.2 ). ^{, , ,} In one study, loss of neuroendocrine cells in the intestinal crypts was observed in 78% of small-bowel and/or colon biopsies in AIE patients; occasional loss (9%) was observed in CVID patients, while neuroendocrine cell density was intact in patients with IBD and IgA deficiency. In this study, loss of goblet cells occurred in 89% of cases, whereas loss of Paneth cells occurred in 78%. In some cases, the absence of goblet cells in biopsies coincided with detection of anti–goblet cell antibodies. An absence of plasma cells in the lamina propria may be an indication of concurrent CVID.

In our experience, the features most helpful in suggesting a diagnosis of AIE are villous blunting, lamina propria expansion by mixed but predominantly mononuclear inflammation, neutrophilic activity, patchy increase in intraepithelial lymphocytes, and loss of one of more cell lineages, most often endocrine and goblet cells.

Colon

Colonic involvement has been reported in a relatively large number of cases. ^{, , ,} It affects most patients with AIE and IPEX syndrome. Histological features include lymphoplasmacytic expansion of the lamina propria; neutrophilic cryptitis, either with or without crypt abscesses; and increased apoptosis in crypt epithelium ( Fig. 6.3 ). ^{, ,} Increased apoptosis may be striking, and the predominant feature may be reminiscent of acute GVHD ( Fig. 6.4 ).

Colonic biopsies may exhibit features that are not immediately identifiable as AIE, such as severe colitis with crypt destruction, pyloric metaplasia, and/or crypt atrophy. ^, A lymphocyte-predominant pattern of inflammation that is indistinguishable from lymphocytic colitis may be present as well. One case with thickening of the subepithelial collagen layer in the duodenal mucosa and in the entire colorectal mucosa, which was indistinguishable from collagenous colitis, has also been reported. In our experience, colonic involvement may also be reminiscent of IBD, with crypt architectural irregularities, multinucleated epithelioid giant cells, and Paneth cell metaplasia. However, the full-blown histological features of active chronic colitis of the IBD type are not seen.

Gastric Involvement

Involvement of the stomach may occur in the form of moderate to severe gastritis with expansion of the lamina propria, neutrophils, and apoptotic activity ( Fig. 6.5 ). ^{, , , ,} Active gastritis with glandular destruction has been reported. A lymphocytic gastritis-like pattern has also been reported. Some patients exhibit a peculiar form of atrophic gastritis that resembles autoimmune atrophic gastritis but involves the entire stomach and lacks neuroendocrine cell hyperplasia, distinguishing this disease from autoimmune gastritis. In our experience, the stomach may also exhibit an acute GVHD-like appearance, with near-normal mucosa with increased apoptosis in glandular epithelium, with or without glandular atrophy.