—  SPECIALTY CONFERENCE  —

Gastrointestinal Pathology

Case 1 - Adult-Onset Autoimmune Enteropathy

Susan C. Abraham
Mayo Clinic
Rochester, MN


Click on each slide thumbnail image for an enlarged view
Clinical History
This 36-year-old man was in excellent health until 5 ½ months before the small bowel biopsy was taken. He initially presented with boring epigastric pain and was found to have biochemical evidence of pancreatitis, which required prolonged hospitalization. At the same time he began to pass massive amounts of stool – up to 12 L/day. The diarrhea continued with fasting and ultimately led to a 45-pound weight loss, necessitating TPN.

At the time of his presentation to Mayo Clinic, he had already undergone several small bowel biopsies with negative evaluations for lymphoma including negative molecular studies for clonal T-cell receptor gene rearrangements.

24-hour stool collection resulted in more than 8 kg stool and 97 g fat (normal, 2-7 g/24 hrs). Stool studies for cryptosporidium and other parasites were negative. Laboratory workup was notable for a mildly elevated ANA titer of 2.1 U (normal, <1.0 U). Celiac serology including IgA tissue transglutaminase level was negative, and HLA typing was inconsistent with celiac disease. Moreover, the patient had attempted a gluten-free diet over a 2-month period without relief of his symptoms. Workup for immunodeficiency was negative, including negative HIV serologies and normal immunoglobulin levels for IgG (including normal IgG subclasses), IgA, and IgM.

Upper endoscopy was repeated at Mayo Clinic and the endoscopic appearance of the duodenum and stomach was normal. Abdominal CT scan was notable only for mild mesenteric lymphadenopathy. Because of the concern for small bowel lymphoma and because of the unrevealing workup for the etiology of the patient's severe diarrhea, a decision was made to pursue full-thickness small bowel biopsy. The section shown is taken from the full-thickness jejunal biopsy, which was obtained laparoscopically.


Case 1 - Figure 1 - Jejunal biopsy shows marked villous blunting and intense mucosal inflammation.
Case 1 - Figure 2 - Scattered crypt abscesses are present.
Case 1 - Figure 3 - Crypt bases are lifted from the muscularis mucosa by a dense band of chronic inflammation including lymphocytes, plasma cells, and eosinophils. Crypts lack goblet cells and Paneth cells and are replaced in many foci by areas of pseudopyloric metaplasia.


Case 1 - Figure 4 - Some crypts (e.g., at center) show features resembling graft-vs.-host disease, with increased numbers of apoptotic bodies and infiltration of crypt epithelium by lymphocytes.
Case 1 - Figure 5 - The surface epithelium is severely injured, with a disorganized appearance. The degree of surface intra-epithelial lymphocytosis (in contrast to celiac disease) is quite mild.
Case 1 - Figure 6 - Low power view of the full-thickness small bowel biopsy highlights a complete lack of transmural inflammation.

Microscopic Examination:
Marked architectural and cytologic abnormalities were present. Architecturally, there was severe villous blunting, but the surface epithelium lacked the heavy intra-epithelial lymphocytosis characteristic for celiac disease. Lamina propria was expanded by dense lymphoplasmacytic infiltrates with crypt shortfall and basal plasmacytosis. Deep crypts were infiltrated by increased numbers of small lymphocytes and there was a mild increase in crypt apoptosis; again, these changes spared the surface epithelium. A component of active inflammation was also present including crypt abscess formation. Cytologically, the normal small bowel epithelium was replaced by a simplified type of columnar epithelium which completely lacked goblet cells and Paneth cells. Deep crypts were replaced by extensive pseudopyloric metaplasia, while the surface epithelium was notable for a disorganized, injured appearance and lack of a well-formed brush border. All of these abnormalities were confined to the mucosa; there was a complete lack of transmural inflammation, and there were no granulomas.

Follow-up:
The patient's serum was sent to Children's Hospital of Philadelphia (CHOP). Anti-enterocyte antibody testing was performed by indirect immunofluorescence on normal human small bowel using the patient's serum as a first stage and FITC-conjugated IgG, IgM, and IgA on sequential slides as a second stage. The result for IgG was positive at serum dilutions up to 1:200.

The patient was started on oral prednisone at 30 mg/d and then 60 mg/d with little benefit. A decision was subsequently made to institute Imuran therapy at 150 mg/d.

Diagnosis: Adult-onset autoimmune enteropathy.

Discussion:
Autoimmune enteropathy is most common (and was originally described) in children – typically boys under one year of age but older than 8 weeks. A subset of these children suffer from a systemic, familial syndrome of autoimmunity: IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linkage) syndrome. IPEX syndrome results from germline mutations in the FOXP3 gene on the X-chromosome. The protein product of FOXP3, scurfin, is a transcription factor involved in the proliferation of CD4+ T-cells, and affected children typically suffer from the sequellae of organ infiltration and destruction by activated T-cells including young-onset type I diabetes, autoimmune enteritis or allergic (eosinophilic) enteritis, autoimmune thyroiditis, hemolytic anemia, and eczema. It is now recommended that boys with autoimmune enteropathy and one or more of these other manifestations – and particularly boys with a similarly affected sibling – be tested for mutations in FOXP3. In the last few years, allogeneic bone marrow transplantation has been reported to be curative for IPEX syndrome.

Clinically, children and adults with autoimmune enteropathy suffer from prolonged, intractable diarrhea which is secretory in nature and characteristically does not respond to bowel rest/TPN use. Many patients have other, systemic, autoimmune conditions which can variably include insulin-dependent diabetes, renal disease (membranous glomerulopathy with granular IgG deposits and/or interstitial nephritis with linear IgG along tubular basement membranes), thyroiditis, autoimmune hepatitis, Coombs+ hemolytic anemia, etc. Additionally, investigation of the serum of many patients (even those who do not have clinical manifestations of these other autoimmune diseases) will reveal circulating autoantibodies such as ASMA, ANA, anti-LKM (in patients with liver disease), anti-islet cell antibodies, anti-parietal cell antibodies, etc.

There are two forms of autoimmune enteropathy which differ in their histopathology and autoantibody status. The more common form is illustrated by the current patient and is characterized by the presence of a circulating anti-enterocyte antibody which reacts against normal enterocytes of human intestine as well as enterocytes from other animal species. These antibodies result in a linear pattern of staining along the apical (brush border) aspect of enterocytes with extension along the basolateral enterocyte borders. Usually the anti-enterocyte antibodies are IgG type although IgA and IgM can also occur. The antibody tends to disappear following successful therapy, even before histologic normalization of the mucosa. Histologically, patients with this form of autoimmune enteropathy have villous atrophy (often severe); this can be accompanied either by crypt hyperplasia, as in celiac disease, or crypt hypoplasia. The lamina propria is expanded by mixed active and chronic inflammatory infiltrates that are typically rich in CD4+ T-cells. The deep crypts may show a pattern reminiscent of graft-vs.-host disease with lymphocytic infiltration and increased crypt apoptotic bodies. The main feature on H&E stain that distinguishes this form of autoimmune enteropathy from celiac disease is the relative paucity of intraepithelial T-cells in the surface epithelium in autoimmune enteropathy as compared to celiac disease. Immunophenotypically, T-cells in autoimmune enteropathy express TCR ab, whereas in celiac disease they are predominantly TCRgd in type.

The less common form of autoimmune enteropathy is characterized by circulating anti-goblet cell antibodies. Indirect immunofluorescence using the patient's serum applied to frozen sections of normal human intestine is used to demonstrate these antibodies by revealing staining in goblet cell mucus. Anti-goblet cell antibodies are considered to be less specific than anti-enterocyte antibodies; one report from Japan found them in up to 30% of patients with chronic IBD. Clinical features in these patients are similar to those listed above, but the histolopathologic features of small intestinal biopsies are distinctive. The villous architecture is preserved and the biopsies may at first appear relatively normal unless one recognizes the absence of goblet cells, Paneth cells, and (in some reports) endocrine cells. In two (adult) cases in our experience, there was also a pattern of lymphocytic attack and increased apoptosis in deep crypts, but only a minimal increase in surface lymphocytosis. The brush border is intact and the surface enterocytes are morphologically normal.

Some investigators have speculated that anti-enterocyte and anti-goblet cell antibodies might represent an epiphenomenon resulting from mucosal injury rather than a pathogenetic mechanism of autoimmune enteropathy. First, some patients fulfill clinical and morphologic criteria for autoimmune enteropathy in the absence of demonstrable anti-intestinal antibodies. Second, the antibodies tend to occur after the onset of disease and tend to disappear before the before the intestinal morphology has normalized.

Many patients with autoimmune enteropathy have a generalized autoimmune gut disease that affects the colon and (a bit less commonly) the stomach as well as small bowel. The colitis resembles the patient's enteritis, with deep lamina propria inflammation, crypt destruction/dropout, and a relative paucity of surface lymphocytosis. Patients with anti-goblet cell antibodies also lack goblet cells and Paneth cells in the colon and terminal ileum. Gastric pathology in these patients has been less well-described. One adult patient at our institution with anti-goblet cell-associated autoimmune enteritis and colitis had a distinctive and severe gastritis that was characterized by:

  1. absence of Helicobacter pylori
  2. involvement of both antrum and body
  3. intense active chronic inflammatory infiltrates, again with a deep component to the inflammation
  4. near-complete destruction of the specialized oxyntic and pyloric glands and replacement of the normal gastric epithelium by a simplified type of columnar epithelium.


How uncommon is autoimmune enteropathy? It is certainly a rare condition, but probably less rare than the literature would suggest, since it is likely an under-recognized disease. Most pathologists and gastroenterologists (particularly those dealing primarily with adults) have little or no experience with the disease and do not consider it in their differential diagnosis. Common morphologic mistakes include misclassification of small bowel biopsies as Crohn's disease, celiac disease, or generic "duodenitis." The absence of goblet cells can go unrecognized unless one specifically looks for them in the biopsies. Furthermore, testing for anti-enterocyte and anti-goblet cell antibodies is confined to a few specialized institutions, making routine investigations for these antibodies difficult.

In a review article on refractory celiac disease several years ago (Gastroenterology 2000;119:243-51), autoimmune enteropathy was described as one potential cause – the authors cited 2 published reports in which anti-enterocyte antibodies were found in 60% (3 of 5) adult patients with refractory sprue – leading to the suggestion that autoimmune enteropathy should be screened for in all patients with refractory sprue.

Autoimmune enteritis is a life-threatening condition that can cause death by malnutrition or dehydration. Treatment, unfortunately, can be problematic. Many patients do not respond to corticosteroids alone or require high doses for maintenance. A variety of other immunosuppressive agents have been tried including tacrolimus, cyclosporine, methotrexate, azathyioprine, etc., with varying success.

References

  1. Beck NS, Kang IS, Suh YL. Protracted diarrhea: results of the five-year survey in a tertiary hospital in Korea. J Korean Med Sci 2001;16:736-41.
  2. Colletti RB, Guillot AP, Rosen S, et al. Autoimmune enteropathy and nephropathy with circulating anti-epithelial cell antibodies. J Pediatr 1991;118:858-64.
  3. Daum S, Sahin E, Jansen A, et al. Adult autoimmune enteropathy treated successfully with tacrolimus. Digestion 2003;68:86-90.
  4. Hori K, Fukuda Y, Tomita T, et al. Intestinal goblet cell autoantibody associated enteropathy. J Clin Pathol 2003;56:629-30.
  5. Leon F, Olivencia P, Rodriguez-Pena R, et al. Clinical and immunological features of adult-onset generalized autoimmune gut disorder. Am J Gastroenterol 2004;99:1563-71.
  6. Moore L, Xu X, Davidson G, et al. Autoimmune enteropathy with anti-goblet cell antibodies. Hum Pathol 1995;26:1162-8.
  7. Russo PA, Brochu P, Seidman EG, Roy CC. Autoimmune enteropathy. Pediatr Dev Pathol 1999;2:65-71.
  8. Ryan BM, Kelleher D. Refractory celiac disease. Gastroenterology 2000;119:243-51.
  9. Sherman PM, Mitchell DJ, Cutz E. Neonatal enteropathies: defining the cause of protracted diarrhea of infancy. J Pediatr Gastroenterol Nutr 2004;38:16-26.
  10. Thomas AG, Phillips AD, Walker-Smith JA. The value of proximal small intestinal biopsy in the differential diagnosis of chronic diarrhoea. Arch Dis Child 1992;67:741-3.