Dr. Francis P. Colizzo: I participated in the care of this patient and am aware of the final diagnosis. This 33-year-old man had a long-standing diagnosis of autoimmune enteropathy, which had been complicated by hemolytic anemia, membranous nephropathy with proteinuria, and eczema. Symptoms were intermittently controlled with the administration of glucocorticoids and other immunosuppressive agents, but full and durable remission was never established. Could the patient’s current presentation with relapsing diarrhea be caused by persistence or exacerbation of his primary condition, autoimmune enteropathy? Or could it be caused by another condition that he acquired because of chronic immunosuppression? Alternatively, could his diagnosis of autoimmune enteropathy, which he had carried for most of his life, be incorrect? The first step in caring for this patient is to reconsider the differential diagnosis of chronic diarrhea and malabsorption that can occur in association with villous atrophy and enteropathy.
Autoimmune enteropathy is a rare condition that is more common among infants and children than among adults. It can occur as a primary process or be due to another immune-mediated process. Symptoms include chronic diarrhea, malabsorption, and weight loss. Extraintestinal manifestations can include hemolytic anemia, nephritis, and dermatitis, all of which had occurred in this patient. Thyroiditis and hepatitis have also been reported as extraintestinal manifestations of autoimmune enteropathy.
The proposed diagnostic criteria for autoimmune enteropathy include the detection of villous atrophy on biopsy of the small intestine, along with a decrease in goblet cells in the tissue; the presence of antienterocyte antibodies; and chronic diarrhea with malabsorption.1 Anti–epithelial cell antibodies had been detected in this patient when he was 4 years of age. At that time, antienterocyte antibody testing was not yet available, and the patient met criteria for the diagnosis of autoimmune enteropathy. When I initially evaluated this patient, serum testing for antienterocyte antibodies was positive at a titer of 1:10. However, potential causes other than autoimmune enteropathy were considered, given the refractory nature of the diarrhea and the other substantial clinical symptoms.
Patients with celiac disease also have diarrhea, malabsorption, and weight loss. Extraintestinal manifestations can include IgA nephropathy and dermatitis herpetiformis, neither of which had occurred in this patient. In addition, celiac disease is not typically associated with hemolytic anemia,2 which had been a prominent feature of this patient’s disease course.
In patients with celiac disease, serologic evaluation confirms the presence of tissue transglutaminase IgA; if the patient has selective IgA deficiency, tissue transglutaminase IgG can be measured. In this patient, serologic testing for tissue transglutaminase IgA was negative in the absence of IgA deficiency. Furthermore, celiac disease is treated with elimination of gluten from the diet, and this patient’s symptoms did not abate with dietary gluten elimination. Collagenous sprue is a rare subtype of celiac disease that is often refractory to conventional treatment, but it is characterized by the presence of a subepithelial collagen band on histopathological examination of a biopsy specimen from the small intestine, a finding that was not seen in this patient.
Inflammatory Bowel Disease
Inflammatory bowel disease can cause diarrhea and malabsorption, but it rarely develops in infancy. However, an entity described as very-early-onset inflammatory bowel disease has been reported; it has been associated with certain genetic variants.3 Although inflammatory bowel disease is not typically associated with renal manifestations, granulomatous interstitial nephritis and IgA nephropathy have been reported in some patients with inflammatory bowel disease.4,5 This patient had no evidence of inflammatory bowel disease on endoscopy, and his fecal calprotectin level was normal.
Small-Intestinal Bacterial Overgrowth
Small-intestinal bacterial overgrowth is a condition characterized by bloating, diarrhea, and cramping. It is caused by excessive small-bowel colonization with colonic microbes and is treated with oral antibiotic agents. This patient had no confirmed underlying conditions that are known to confer a predisposition to small-intestinal bacterial overgrowth, such as inflammatory bowel disease, diverticula in the small intestine, intestinal resections, motility disorders, diabetes, scleroderma, or IgA deficiency. In addition, his extraintestinal manifestations would not be explained by small-intestinal bacterial overgrowth. A lactulose breath test was negative, which argues against this diagnosis, but because carbohydrate breath tests have variable sensitivity and specificity, this finding does not rule out small-intestinal bacterial overgrowth.
Intolerance of Cow’s Milk
Cow’s milk intolerance is common among infants and young children. It causes diarrhea and can be associated with eczema. Cow’s milk intolerance usually resolves with age, whereas this patient’s symptoms persisted into adulthood. In addition, skin-prick testing with cow’s milk antigen was negative, and symptoms persisted despite elimination of cow’s milk from the diet.
Eosinophilic gastroenteritis is most prevalent among children younger than 5 years of age and is often associated with a coexisting atopic condition. Because there is usually an underlying allergic component, eosinophilia and an elevated blood IgE level can be present. The blood IgE level was sometimes elevated in this patient, and the absence of eosinophilia could be explained by ongoing treatment with glucocorticoids. However, there was no evidence of tissue involvement with eosinophilic infiltration in the mucosa or muscularis layers on multiple biopsies of the small intestine.
Enteropathy Associated with Angiotensin-Receptor Blockers
Sprue-like enteropathy has been reported in patients taking the angiotension II–receptor blocker olmesartan. There have been very few case reports of this condition occurring with the use of losartan,6 which was the angiotension II–receptor blocker that this patient was taking. This patient’s symptoms predated his use of losartan, so this medication is unlikely to be the cause of his symptoms; however, a brief trial involving discontinuation of this medication would be appropriate.
Inborn Errors of Immunity
Inborn errors of immunity, also known as primary immunodeficiencies, are disorders that stem from defects in immune regulation or tolerance and can mimic inflammatory bowel disease. Many of these conditions can be fatal early in life. The most common primary immunodeficiency — common variable immune deficiency — can be ruled out in this patient, given the absence of immunoglobulin deficiencies. Two additional primary immunodeficiencies merit consideration in this patient: autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) and immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome.
APECED, also known as autoimmune polyendocrine syndrome type 1 (APS-1), results from a defect in the autoimmune regulator gene (AIRE) that leads to a loss of central immune tolerance.7 Patients with APECED present with mucocutaneous candidiasis, ectodermal dystrophy, and multiple endocrine diseases. Hypoparathyroidism and adrenal insufficiency are the most common endocrine diseases; diabetes mellitus or hypothyroidism (or both) can also occur. APECED is often associated with underlying autoimmune enteropathy, and gastrointestinal manifestations can vary widely. However, this patient did not have any of the typical endocrine diseases associated with APECED or have mucocutaneous candidiasis.
IPEX syndrome is an immune dysregulatory disorder that typically develops in infancy. It is due to a defect in the gene encoding forkhead box protein 3 (FOXP3) that leads to dysfunctional regulatory T cells.8 Patients with IPEX syndrome present with a classic triad of manifestations: autoimmune endocrinopathies (typically neonatal type 1 diabetes mellitus and thyroiditis), autoimmune enteropathy (associated with failure to thrive and severe chronic diarrhea), and eczematous dermatitis. Hemolytic anemia and nephritis, which were seen in this patient, have been described in patients with IPEX syndrome. Intestinal biopsy typically reveals features consistent with autoimmune enteropathy: villous atrophy, intraepithelial lymphocytes, and plasma cells. Immunosuppressive therapy is the mainstay of treatment. However, immunosuppression typically controls symptoms only transiently, without long-term remission, which is consistent with this patient’s disease course.
Given this patient’s history, clinical presentation, and constellation of symptoms, I suspected that IPEX syndrome was the most likely diagnosis. To establish this diagnosis, I referred the patient to the allergy and clinical immunology unit for further evaluation and consideration for genetic testing.