* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Gastrointestinal Manifestations in APECED Syndrome
Cancer immunotherapy wikipedia , lookup
Globalization and disease wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Childhood immunizations in the United States wikipedia , lookup
Rheumatic fever wikipedia , lookup
Ulcerative colitis wikipedia , lookup
Hospital-acquired infection wikipedia , lookup
Gastroenteritis wikipedia , lookup
Myasthenia gravis wikipedia , lookup
Signs and symptoms of Graves' disease wikipedia , lookup
Behçet's disease wikipedia , lookup
Rheumatoid arthritis wikipedia , lookup
Inflammatory bowel disease wikipedia , lookup
Neuromyelitis optica wikipedia , lookup
Multiple sclerosis research wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Traveler's diarrhea wikipedia , lookup
Molecular mimicry wikipedia , lookup
Multiple sclerosis signs and symptoms wikipedia , lookup
Management of multiple sclerosis wikipedia , lookup
Immunosuppressive drug wikipedia , lookup
CLINICAL REVIEW Gastrointestinal Manifestations in APECED Syndrome Nicolas Kluger, MD,* Martta Jokinen, MC,* Kai Krohn, MD, PhD,w and Annamari Ranki, MD, PhD* Abstract: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (or autoimmune polyendocrine syndrome type 1) is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator gene. It causes a loss in central immune tolerance, failure to eliminate autoreactive T cells in the thymus, and their escape to the periphery. APECED patients are susceptible to mucocutaneous candidiasis and multiple endocrine and nonendocrine autoimmune diseases. Although it depends on the series, approximately 25% of APECED patients are affected by gastrointestinal (GI) manifestations, mainly autoimmune-related disorders like autoimmune hepatitis, atrophic gastritis with or without pernicious anemia (Biermer disease), intestinal infections, and malabsorption. In contrast to the major organ-specific autoimmune symptoms of APECED, the GI symptoms and their underlying pathogenesis are poorly understood. Yet isolated case reports and small series depict severe intestinal involvement in children, leading to malabsorption, multiple deficiencies, growth impairment, and possible death. Moreover, very few systematic studies of GI function with intestinal biopsies have been performed. GI symptoms may be the first manifestation of APECED, yet they may have various causes; effective treatment will therefore vary. We provide here an updated review of GI manifestations in APECED, including principles of diagnosis and therapy. Key Words: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, autoimmune polyendocrine syndrome type 1, gastritis, Biermer disease, hypoparathyroidism, diarrhea, autoimmune enteropathy (J Clin Gastroenterol 2013;47:112–120) A utoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, OMIM 240300), also called autoimmune polyendocrine syndrome type 1, is a rare autosomal recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene located on chromosome 21 (21q22.3).1–3 AIRE deficiency causes a loss in central immune tolerance, leading to the failure to eliminate autoreactive T cells in the thymus and allowing their escape to the periphery.3 Because of a founder effect, APECED is particularly prevalent in Finland (1/25,000)2,4 but is observed worldwide with variable prevalence.5–16 APECED patients are susceptible to mucocutaneous candidiasis and multiple endocrine autoimmune diseases such as From the *Departments of Dermatology, Allergology and Venereology, Institute of Clinical Medicine, University of Helsinki, and Skin and Allergy Hospital, Helsinki University Central Hospital; and wClinical Research Institute HUCH Ltd, Helsinki, Finland. Supported by the European Science Foundation (ESF) and the Sigrid Juselius foundation. The authors declare that they have nothing to disclose. Reprints: Nicolas Kluger, MD, Departments of Dermatology, Allergology and Venereology, Skin and Allergy Hospital, Helsinki University Central Hospital, Meilahdentie 2, P.O. Box 160, Helsinki FI-00029, Finland (e-mail: [email protected]). Copyright r 2013 by Lippincott Williams & Wilkins 112 | www.jcge.com adrenocortical insufficiency (Addison disease), primary hypoparathyroidism (HP), primary hypogonadism, type I diabetes, hypothyroidism, and hypophysitis. They may also develop additional nonendocrine autoimmune diseases, such as alopecia areata/totalis, vitiligo, nephritis, and keratitis.1 Gastrointestinal (GI) manifestations are included in the group of “minor” components of APECED and have been reported since the 1950s.9 They include mainly autoimmune-related disorders like autoimmune hepatitis,17 atrophic gastritis with or without pernicious anemia (Biermer disease), intestinal infections, and malabsorption. In contrast to the major organ-specific autoimmune symptoms of APECED, the GI symptoms and their underlying pathogenesis are poorly understood. However, clinical studies estimate the prevalence of GI symptoms and signs (excluding hepatitis) up to roughly 25%, and both cohort and review articles usually describe GI manifestations as “diarrhea,” “constipation,” and “malabsorption.”1,18 Conversely, isolated case reports and small series have depicted severe intestinal involvement in children leading to malabsorption, multiple deficiencies, growth impairment,19 and possible death.2 Moreover, there are very few systematic studies of GI function with intestinal biopsies. GI symptoms may be the first manifestation of APECED and the causes may vary; therefore, effective treatment will vary accordingly. We provide here an updated review of GI manifestations in APECED, including principles of diagnosis and therapy. All the GI manifestations are summarized in Tables 1 and 2. ESOPHAGEAL SYMPTOMS: CANDIDIASIS AND ESOPHAGEAL CARCINOMA Chronic mucocutaneous candidiasis (CMC) is one of the “triad” symptoms characterizing APECED, the others being HP and adrenocortical failure.1–3,5 Although APECED is one of the primary immunodeficiencies leading to CMC, it is not the only one.21 Candida infection in APECED patients affects the nails and the oral, vaginal, and esophageal mucosa.3 Interestingly, patients with APECED display selective immunodeficiency to Candida but not to other fungi or bacteria. Systemic dissemination with potential lethal outcome is possible but quite rare and mostly because of additional iatrogenic factors such as immunosuppressive therapies.8 Immunity to Candida involves both innate and adaptive mechanisms; however, an alteration in T-cell cytokine secretion seems to be crucial for the predisposition. An impaired Th1 response leads to increased susceptibility to severe Candida infection,21 and recent studies have shown that Th17 lymphocytes are essential for Candida resistance.22 Th17 lymphocytes secrete interleukin (IL)-17A, IL-17F, IL-21, IL-22, and IL-26, all of which are involved in recruiting neutrophils and protecting against bacterial and fungal infections.23,24 In CMC, type 1 cytokines [interferon (IFN)g, IL-12, and IL-2] are diminished, J Clin Gastroenterol Volume 47, Number 2, February 2013 J Clin Gastroenterol Volume 47, Number 2, February 2013 TABLE 1. A Review of Gastrointestinal Manifestations During APECED Esophagus Candida esophagitis Esophageal carcinoma Stomach Pernicious anemia (Biermer anemia) Autoimmune gastric atrophy Gastric adenocarcinoma Gastric carcinoid tumor Bowel Primary hypoparathyroid-induced hypocalcemia Secondary hypocalcemia due to malabsorption of vitamin D Intestinal infection: bacterial overgrowth, Candida infection, Giardiasis lamblia, Clostridium difficile Exocrine pancreatic insufficiency: hypocalcemia, diabetes, celiac disease, cystic fibrosis, intestinal megaloblastosis due to vitamin B12 deficiency, autoimmune pancreatitis associated or not to AE* Autoimmune enteropathy Lactase nonpersistance/deficiency Intestinal lymphangiectasia Celiac disease Functional disease Autoimmune hepatitis Cholelithiasis *No case reported in APECED thus far, but considered according to the pancreatitis induced in the knockout Aire / mouse model.20 APECED indicates autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. whereas type 2 cytokines (IL-4, IL-10) are elevated and work concurrently to diminish antimicrobial peptide production and recruit neutrophils in situ.25,26 Interestingly, APECED patients have circulating antibodies against type 1 cytokines such as IFN-o and IFN-a (100% and 95% of cases), IL-22 (> 90% of cases), and IL-17 (75%).24 The prevalence, age of presentation, and severity of CMC in APECED is variable,5,7,16 most likely resulting from differential mutations of the AIRE gene.24 Overall, IL-17 and IL-22 seem to be key cytokines implicated in the CMC of APECED patients. Nevertheless, further studies are warranted to clarify whether other components of anti-Candida immunity, such as human epithelial defensins, are impaired in APECED. Oral candidiasis usually presents with pseudomembranotic lesions, erosion, ulceration, and pain. Candida esophagitis has been reported to affect 15% to 22% of APECED patients,2,24 with pain while swallowing, retrosternal pain, and dysphagia (Fig. 2, see page 118).3,5 Symptoms may be improved by antifungal treatment.2,5 Oral candidiasis is not always associated with esophageal candidiasis.2,16 Chronic inflammation may lead to esophageal stricture,2,5,8,16 which requires treatment with balloon dilatation or stenting. Oral and esophageal carcinoma may develop over the long term as a complication of chronic inflammation mediated by CMC. Alcohol intake and active smoking are additional risk factors that may promote carcinogenesis.27 In the Finnish series of 92 patients, only one 40-year-old male patient, with a history of severe chronic oral candidiasis since infancy, smoking, and alcohol drinking, developed esophageal carcinoma. Dysphagia and r 2013 Lippincott Williams & Wilkins Gastrointestinal Manifestations in APECED Syndrome retrosternal pain developed 6 years after the esophagitis, revealing well-differentiated squamous cell carcinoma leading to death 18 months later.28 Of note, esophageal cancer during CMC without APECED has been reported,27,29 indicating that chronic candidiasis plays a role in carcinogenesis rather than APECED itself. The management of candidiasis in APECED patients is based on excellent oral hygiene with careful and regular dental follow-up. Dental plaque should be treated actively, as it may be the source of yeast in the oral cavity. Candidiasis should be treated aggressively with antimicrobial therapy and regular prophylaxis should be given. Azoles, fluconazole especially, are usually recommended as the first-line treatment but often lead to selective resistant strains.21,30–32 Therefore, regular fungal sensitivity tests should be performed. Topical polyenes (amphotericin B) are preferable, as they are less prone to selecting resistant Candida strains.28 Echinocandins are available by intravenous infusion but systemic polyene (amphotericin B) should be restricted to systemic Candida infection, given its potential side effects.21 Any suspicious lesions, erosion that does not heal, or thickening, leukoplakia especially, should be biopsied. Difficulties in swallowing or eating and retrosternal pain should also prompt an esophagoscopic examination.28 GASTRIC SYMPTOMS: CHRONIC GASTRITIS AND PERNICIOUS ANEMIA Chronic atrophic gastritis is an autoimmune disease affecting the gastric parietal cells and intrinsic factor (IF). It eventually leads to gastric atrophy, which in turn is associated with vitamin B12 deficiency and pernicious anemia (PA, Biermer disease).33 The chronic gastritis seen in APECED is of the A type, which, according to the Strickland classification, is based on an autoimmune response to the gastric mucosa. In contrast, the B type of gastritis, thought to be originally caused by environmental factors, is in most cases the consequence of chronic infection with Helicobacter pylori. Patients with A type gastritis have antibodies against the sodium-potassium channel molecule of the parietal cells in the corpus and fundus of the stomach (parietal cell antibodies).34,35 The process starts with superficial gastritis, characterized by lymphocytic infiltration below the epithelium that does not reach specific glands. A diffuse gastritis then follows with lymphocytic infiltration extending to specific glands and to glandular destruction (atrophic gastritis). In the final stage, hydrochloric acid and pepsinogen-producing cells have disappeared, as has the secretion of gastric IF. PA is thus the end stage of gastric immunologic destruction, caused not only by the lack of IF, but also by autoantibodies recognizing this vitamin B12-binding protein and preventing the subsequent translocation of vitamin B12 from the ileum to circulation.33 Chronic gastritis and PA may occur as solitary conditions or associated with various autoimmune endocrinopathies and antireceptor autoimmune diseases.33 These conditions have been reported in approximately 30% of the APECED patients in Finland.2 According to other series, the prevalence in APECED patients ranges from 9% to 27%.6–16,36 The circulating antibodies reacting with parietal cells and IF may be detected before any clinical symptoms.2 PA usually develops during early adulthood,8 although sometimes in early childhood,37 which differs from the solitary PA, usually diagnosed in the sixth decade.33 One reason for the diagnosis at an earlier age may be www.jcge.com | 113 J Clin Gastroenterol Kluger et al Volume 47, Number 2, February 2013 TABLE 2. Manifestations and Mechanisms of the Main Gastrointestinal Disease of APECED Esophagus Esophagitis Esophageal carcinoma Stomach Pernicious anemia (Biermer anemia) Autoimmune gastric atrophy (type A) Gut Primary hypoparathyroidism Hypocalcemia Intestinal infections Symptoms Etiology Antibodies/Targets* Treatment Retrosternal pain, dysphagia Difficulty to eat, vomiting Candida infection None Antifungal therapy Chronic inflammation None Surgery, chemotherapy, stenting B12 deficiency Autoimmunity B12 supplementation None Autoimmunity Antibodies against sodiumpotassium channel molecule of the parietal cells and intrinsic factor Antibodies against parietal cell and intrinsic factor Chronic diarrhea, hypocalcemia, low parathormone Autoimmunity Chronic diarrhea, hypocalcemia, normal parathormone Chronic diarrhea Vitamin D deficiency related to intestinal malabsorptionw Exocrine pancreatic insufficiency Chronic diarrhea Autoimmune enteropathy Chronic diarrhea Bacterial or parasitic infestation Multiple: hypocalcemia, diabetes, celiac disease, cystic fibrosis, vitamin B12 deficiency (intestinal megaloblastosis) Autoimmunity Chronic diarrhea after milk and dairy product consumption Chronic diarrhea Autoimmunity Lactose intolerance Celiac disease No treatment if no B12 deficiency Antibodies against NALP5 (NACHT leucine-rich repeat protein 5) and calcium sensing receptor antibodies None Calcium and vitamin D supplementation None Antibiotics or antiparasitic treatment Adapted to the culprit cause Depending on the cause Calcium and vitamin D supplementation Antibodies against Immunosuppressive tryptophan hydroxylase and therapies in case of severe histidine decarboxylase symptoms Targets: enteroendocrine cells, Paneth cells, and brush border cells Lactase nonpersistance None Lactose-free diet or deficiency Antibodies against transglutaminase Gluten-free diet *The list of antibodies and targets is not exhaustive and may evolve according to discovery of new targets. wAny cause of intestinal malabsorption. APECED indicates autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. that patients with APECED are closely monitored from infancy or childhood and are therefore more likely to be diagnosed even before clinical symptoms occur. Clinical symptoms of the lack of vitamin B12 may include atrophic glossitis with a smooth red beef tongue, diarrhea, and malabsorption if megaloblastosis affects the intestinal epithelial cells.33 Lack of vitamin B12 affects the synthesis of purines and pyrimidines, leading to deficient DNA synthesis, which results in macrocytosis, anemia, leukopenia, thrombopenia, and pancytopenia. Vitamin B12 deficiency may also cause peripheral neuropathy, degeneration of the spinal cord, and personality defects. Low serum vitamin B12 associated with parietal cell antibodies and IF antibodies is highly evocative of the diagnosis. However, because APECED patients usually have several 114 | www.jcge.com endocrinopathies, their anemia may also be related to Addison disease or hypothyroidism. Therefore, gastric fibroscopy with biopsies remains absolutely mandatory to confirm the presence of type A chronic gastritis. In general, type A autoimmune gastritis affects only the fundus and corpus of the stomach, but spares the antrum.33 The inflammation of the lamina propria eventually leads to intestinal metaplasia that may contribute later to the development of adenocarcinoma.33 Also, as the antrum is spared in PA, gastrin-producing G cells are stimulated by achlorhydria and the reactive hypergastrinemia leads to gastric enteroendocrine cell (EEC) hyperplasia that may lead to the development of carcinoid tumors.33 However, to our knowledge, only Betterle et al8 have reported a case of gastric adenocarcinoma in an APECED patient. Regular r 2013 Lippincott Williams & Wilkins J Clin Gastroenterol Volume 47, Number 2, February 2013 intramuscular injections of vitamin B12 every 1 to 3 months is an essential part of APECED treatment. A rare form of antral gastritis was reported to be linked to autoantibodies reacting with the gastrin-producing cells in the antral mucosa.38,39 Oliva-Hemker et al37 observed in a young APECED patient mild to moderate chronic inflammation on antral biopsies and absence of gastrin secretion. Albeit being a unique case report, it suggests that autoimmune antral gastritis might be possible in APECED patients. DIARRHEA, CONSTIPATION, AND MALABSORPTION Chronic diarrhea is defined as a decrease in stool consistency for >4 weeks and is divided into osmotic, secretory, inflammatory, motility, iatrogenic, and functional diseases.40 However, diarrhea is rarely unifactorial and several mechanisms may overlap. Diarrhea in the context of malabsorption displays several characteristics: excess gas; weight loss; and fatty-appearing, foul-smelling, light-colored, and greasy, floating or undigested stools that are difficult to flush. The inflammatory diarrhea in inflammatory bowel disease or invasive bacterial infections is associated with blood and pus in the stools.41 Therefore, the first step to a precise diagnosis of chronic diarrhea requires a careful clinical history and examination.40 Interestingly, such precisions on the type of diarrhea are often lacking in the APECED literature. Chronic diarrhea is the first manifestation of APECED in 5% of patients and severe constipation in 2%,2 whereas malabsorption varies from 9% to 26%, according to the series.5,8,9,14 Meloni et al16 recently reported that approximately half of their Sardinian patients showed periodic intestinal dysfunction. The precise identification of the cause of intestinal symptoms in association with APECED, that is, abdominal pain; bloating; and recurrent, watery or fatty (steatorrhea) diarrhea or constipation, is a real challenge for the physician as it is far from obvious. Several disorders may co-occur or may follow successively over the patient’s lifetime. Therefore, each new episode may be related to either a previously identified cause or a new one that has not yet been diagnosed. Reports on APECED patient cohorts often lack precision in this regard, and varying criteria have been chosen to define GI manifestations. Authors may also evaluate only 1 aspect of GI symptoms. For instance, Ahonen et al5 focused only on malabsorption defined as floating stools and increased fecal fat excretion. In this case, other causes of diarrhea in APECED patients, as seen above, would be missed. Often, the precise cause of malabsorption has not been fully analyzed5,12 or it may have been multifactorial.14 We next discuss the known causes of GI symptoms in APECED patients. Autoimmune HP The parathyroid glands are involved in calcium regulation through the secretion of parathormone (PTH). Acquired autoimmune HP is one of the cardinal manifestations of APECED3,5 and affects approximately 80% of patients.2,16 It may start early in life5 and cause hypocalcemia and hyperphosphatemia. The main GI manifestations of HP, irrespective of its cause, are steatorrhea and diarrhea.42,43 Therefore, diarrhea may be the first symptom r 2013 Lippincott Williams & Wilkins Gastrointestinal Manifestations in APECED Syndrome of hypocalcemia and HP in APECED.2,5 Symptoms tend to recur whenever the patient has hypocalcemia1–3; however, not all patients with hypocalcemia develop diarrhea.1 Steatorrhea is due to the insufficient endogenous secretion of cholecystokinin by the duodenal mucosa during a meal. Cholecystokinin stimulates normal gallbladder contraction and pancreatic enzyme secretion.44 Steatorrhea occurs as a consequence of biliopancreatic exocrine deficit. Management includes a medium-chain triglyceride diet and correction of HP by administration of vitamin D and normalization of hypocalcemia.43 A clue for the diagnosis of HP-related steatorrhea is hyperphosphatemia. Hypocalcemia may also cause watery diarrhea without steatorrhea.45 Therefore, hypocalcemia should be systematically checked for any APECED patient with either diarrhea or steatorrhea. A minority of APECED patients may not have autoimmune HP. Hypocalcemia then becomes the consequence and not the cause of steatorrhea. In this case, serum levels of phosphorus are normal or low because of reactive secondary secretion of PTH.42 Finally, a vicious circle may develop: hypocalcemia related to HP is responsible for steatorrhea, which in turn maintains hypocalcemia by malabsorption and the absence of PTH secretion.2 Interestingly, the GI manifestations of hypocalcemia do not seem to be well known and may be overlooked, as illustrated by the case of a man with a long history of APECED and HP, who developed diarrhea and steatorrhea at the age of 34 years. It was then revealed that the episodes occurred in association with hypocalcemia.46 The authors further reported that staining of chromogranin and cholecystokinin from the duodenum were negative but no circulating antibodies against EECs or cholecystokinin-producing cells were found. Cholecystokinin immunopositivity and secretion were reversed with a medium-chain triglyceride diet. The authors hypothesized various underlying mechanisms but did not consider hypocalcemia as a cause of malabsorption. It may be speculated that the hypocalcemia, in relation to the HP, was mainly responsible for the diarrhea, which improved by oral calcium intake and the mediumchain triglyceride diet. The absence of EECs as a result of autoimmune enteropathy (AE) may also have played a role. AE AE, first described in 1982, is a rare autoimmune disorder affecting mainly children. It is characterized by: (i) protracted diarrhea and severe enteropathy with small-intestinal villous atrophy; (ii) no response to exclusion diets; (iii) evidence of a predisposition to autoimmune disease (circulating enterocyte antibodies or associated autoimmune diseases); and (iv) no severe immunodeficiency.47–49 Autoantibodies against intestinal brush border, enterocyte cytoplasm, goblet cells, and a 75-kDa antigen located in the gut and kidney (AE 75) are detected in association with AE.49 Moreover, AE is one of the main features of immune dysfunction, polyendocrinopathy, enteropathy, and X-linked syndrome due to mutation in the FOXP3 gene on the X chromosome. The FOXP3 mutation leads to a loss of function of CD4 + CD25 + T-regulatory cells, which are implicated in the maintenance of self-tolerance. Interestingly, APECED and X-linked syndrome are both polyglandular syndromes with immune deficiencies, despite different clinical presentations.4 Finally, thymoma, which closely resembles APECED in some aspects,24 has been reported to be associated with AE in rare cases.50 In APECED, AIRE deficiency is responsible for the loss of www.jcge.com | 115 Kluger et al tolerance and autoreactive T cells may escape to the periphery.4 Therefore, it is highly probable that some autoreactive circulating clones can be directed toward intestinal components. Ekwall et al36 identified tryptophane hydroxylase (TPH) as an intestinal autoantigen in APECED patients. TPH is expressed in serotonin-producing cells in the central nervous system and intestine. In their series of 80 patients, they were able to relate “GI symptoms” to the presence of circulating TPH antibodies and also to the total absence of enterochromaffin cells in the mucosa of the small bowel. These EECs are scattered throughout the intestinal mucosa, from the gastric corpus and antrum to the rectum. They play a key role in gut growth, blood flow, motility, and the secretion of pancreatic enzymes, bile and bicarbonate-rich fluid.51 TPH antibodies were detected in 89% of APECED patients with GI symptoms and in 34% of those without.36 Posovszky et al51 found TPH antibody positivity in 3 of their 4 patients with GI symptoms. TPH antibodies sometimes preceded clinical symptoms.36 Conversely, TPH autoantibodies are absent in other inflammatory or autoimmune intestinal diseases such as Crohn’s disease, celiac disease, or AE. In addition, Sköldberg et al52 identified autoantibodies against histidine decarboxylase expressed by EEC-like cells in the gastric mucosa. It should be noted that EEC staining of intestinal biopsies is not a routine procedure in cases of diarrhea or malabsorption, as stressed by Ohsie et al.53 In some cases, GI symptoms are the first or among the first symptoms of APECED.37,51 According to Ahonen et al, 10% of APECED patients present with GI manifestations that then reveal more severe disease.5 Posovszky et al noted that EECs were either initially absent or gradually lost during follow-up in their small series of patients with APECED.51 Several other small series and case reports of APECED patients with GI manifestations have confirmed the absence of EECs along the GI tract with lack of chromogranin A, serotonin, and Grimelius silver staining (Fig. 1).14,19,37,46,51–54 Notably, EECs are not affected in other intestinal diseases with autoimmune background. Oliva-Hemker et al37 and Padeh et al54 found antibodies against EECs and brush borders, respectively, in their patient sera. Paradoxically, the lack of EECs is the main, and if not only, histologic abnormality in the intestines of APECED patients as routine histopathologic analyses show normal-appearing mucosa, absence of villous atrophy and lack of inflammation in the intestinal mucosa.37,51,53 Nevertheless, some authors observed the presence of a mild to moderate unspecific inflammatory infiltrate in the GI mucosa supporting an autoimmune origin.19,37,51 Besides, the efficacy of immunosuppressive therapy on the course of GI symptoms is variable.14,19,51,54 Proust-Lemoine et al14 reported that EECs could be found again under immunosuppressive treatment, but the potential reversibility of EECs may be independent of the treatment, according to some authors.46,51 It should nevertheless be stressed that AE affects mainly children rather than adults. Symptoms are prominent and severe during early childhood and may impair growth.19 It is not clear to what extent AE is similar in adult APECED patients. The existence of AE itself as a distinct entity in adults is also debated.48 Intestinal autoimmunity is only directed toward EECs with a mild inflammatory infiltrate (when seen) in APECED, whereas childhood AE shows aspects close to celiac disease with total villous atrophy, crypt hyperplasia, 116 | www.jcge.com J Clin Gastroenterol Volume 47, Number 2, February 2013 dense lymphoplasmacytic infiltrate into the lamina propria and sometimes crypt abscesses.49 Gastritis is also observed during AE.48,49 Oliva-Hemker et al37 have emphasized the pathologic differences between primary PA and atrophic gastritis in APECED. The possibility of variant forms of AE has recently been stressed.55,56 Al Khalidi et al56 reported the case of a 21-year-old male patient who presented not only villous atrophy and chronic inflammation but also a lack of goblet cells, Paneth cells, and EECs. Therefore, some APECED patients with GI symptoms, children especially, may present a variant form of AE directed strictly against EECs. This type shows clearly distinctive features compared with the “classic” childhood AE and should prompt confirmation by EEC staining and immunosuppressive therapies if necessary. Celiac Disease Celiac disease is an autoimmune disorder affecting approximately 1% of the adults and children in the general population.57 Screening for celiac disease is prompted by unexplained bloating or abdominal distress, chronic diarrhea with or without malabsorption, irritable bowel syndrome, and abnormalities on laboratory tests indicating possible malabsorption. However, celiac disease remains extremely rare in APECED. To date, only Betterle et al8 have reported 2 cases, which represented only 5% of the patients in their series. None of the Finnish APECED patients in our experience has developed this disease. It thus remains unclear whether this association is fortuitous or not. However, we suggest looking systematically for celiac disease during the exploration of an APECED patient with chronic intestinal symptoms. Intestinal Infections Intestinal candidiasis may also be responsible for watery diarrhea and malabsorption.21 As with esophagitis, intestinal infection can occur without concomitant oral candidiasis.2 In their French series of 19 patients, ProustLemoine et al14 found 3 patients (26%) in whom malabsorption improved after antifungal therapy. Besides, one of their young patients had esophageal and colonic candidiasis on fibroscopy and colonoscopy, respectively.14 In cases of abdominal symptoms potentially related to Candidiasis, feces and small bowel aspirates should be examined for intestinal Candida infestation.58 Oral antifungal medications are not always efficient and intravenous therapy may be needed.2 Perheentupa reported the case of a 30-year-old patient with no ascertained deep infection of Candida but who was found at autopsy to have Candida abscesses of the pericardium and small intestine with necrotizing inflammation of the colon and mesenterium.2 The bacterial and parasitic infections that may cause diarrhea include bacterial overgrowth,19 Clostridium difficile2 and Giardiasis59 (Fig. 3). Of note, a 19-year-old female patient died from Campylobacter sepsis in severe coprostasis.2 Pancreatic Exocrine Insufficiency (PEI) PEI typically manifests with steatorrhea and malnutrition. Causes include loss of pancreatic parenchyma (chronic pancreatitis, cystic fibrosis), tumoral pancreatic duct obstruction, decreased pancreatic stimulation (celiac r 2013 Lippincott Williams & Wilkins J Clin Gastroenterol Volume 47, Number 2, February 2013 Gastrointestinal Manifestations in APECED Syndrome FIGURE 1. Immunohistochemistry of colon samples with chromogranin A and serotonin stainings. A, Normal staining of enteroendocrine cells in the colon (chromogranin A staining 10). B, Complete absence of straining of chromogranin A staining ( 10) in the colon of a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). C, Normal staining of enteroendocrine cells in the colon (serotonin staining, 10). D, Complete absence of straining of serotonin staining ( 10) in the colon of a patient with APECED (serotonin staining, 10). r 2013 Lippincott Williams & Wilkins www.jcge.com | 117 Kluger et al J Clin Gastroenterol Volume 47, Number 2, February 2013 and the presence of other symptoms, and diet modification (smaller meals, avoidance of food difficult to digest, fatsoluble vitamin intake).60 Miscellaneous FIGURE 2. Candida infection during esophagitis in an autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patient (Periodic Acid Schiff staining, 20). disease, HP), acid-mediated inactivation of pancreatic enzymes, and GI and pancreatic surgical resections.60 PEI was reported in 4% (5/91) of the Finnish series of APECED patients,2 including 1 patient with defective bile acid reabsorption (1%).13 A few isolated cases have been reported, as well.19,51,54,59 The diagnosis of fat malabsorption is based on the quantification of a fat absorption coefficient after fecal fat determination after 3 days of stool collection.60 Fecal elastase-1 concentration has also proven to be a valuable indirect and noninvasive method for detecting PEI.61 However, various disorders may be responsible for PEI in APECED: hypocalcemia, diabetes19,59—as diabetes has been discussed as a cause of PEI61—and even celiac disease or cystic fibrosis. Therefore, once PEI has been diagnosed, the cause of this deficiency must be determined. Interestingly, Ramsey et al20 observed no microscopic anomaly in the pancreas of their knockout Aire / mice, but 47% of the mouse sera contained autoantibodies against the exocrine pancreas. Therefore, the possibility of genuine autoimmunity against the exocrine pancreas remains a possibility. To the best of our knowledge, no case of autoimmune pancreatitis associated with APECED has ever been reported in humans. Therapy is based on oral intake of exogenous pancreatic enzymes,59 irrespective of the degree of steatorrhea Various other conditions have been described anecdotally. Without the systematic exploration of APECED patients, it is currently unknown whether the following associations are fortuitous or not: cystic fibrosis of the pancreas,62 intestinal lymphangiectasias,14,63,64 and cholelithiasis.8,65 To our knowledge, Ward et al19 reported the only case of hypolactasia, in a 13-year-old girl. However, she also showed bacterial overgrowth and exocrine pancreatic deficiency19 and a lactose-free diet was ineffective. Lactase nonpersistence (adult-type hypolactasia) and lactase deficiency may be confounding factors.66 Finally, despite its fortuitous association with APECED, irritable colon syndrome is sufficiently frequent to justify adding it to the list of differential diagnoses of GI symptoms in APECED patients. CONCLUSIONS GI manifestations have been suggested as a “minor” component of APECED, but they are far from insignificant. In our experience, patients often fail to specifically mention these symptoms and hence they are usually overlooked in the midst of the many signs and symptoms that need to be managed. Difficulties in diagnosis often occur because patients may develop different disorders showing similar symptoms. Moreover, the disorders may be concurrent or occur successively over the patient’s lifetime. Hypocalcemia is the first abnormality that should be screened for and managed in the case of malabsorption in an APECED patient. If there is no hypocalcemia, nor improvement despite efficient management of HP, further explorations are warranted. Autoimmunity should be suspected when anti-infectious agents, normocalcemia, and pancreatic supplementation tablets have not improved the symptoms. EEC immunostaining should be systematically performed whenever intestinal biopsies are obtained in a patient diagnosed with or suspected of having APECED. Overall, the gastroentererologist should be intimately involved in the multidisciplinary care of APECED patients. FIGURE 3. Duodenal biopsies in a autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patient with chronic giardiasis. A, Trophozoites ( 20). B, Trophozoites adherent to the enterocytes ( 20). C, Close-up view ( 40). 118 | www.jcge.com r 2013 Lippincott Williams & Wilkins J Clin Gastroenterol Volume 47, Number 2, February 2013 REFERENCES 1. Perheentupa J. APS-I/APECED: the clinical disease and therapy. Endocrinol Metab Clin North Am. 2002;31:295–320, vi. 2. Perheentupa J. Autoimmune polyendocrinopathy-candidiasisectodermal dystrophy. J Clin Endocrinol Metab. 2006;91: 2843–2850. 3. Husebye ES, Perheentupa J, Rautemaa R, et al. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–529. 4. Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat Rev Endocrinol. 2010;6:270–277. 5. Ahonen P, Myllärniemi S, Sipilä I, et al. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med. 1990;322:1829–1836. 6. Neufeld M, Maclaren NK, Blizzard RM. Two types of autoimmune Addison’s disease associated with different polyglandular autoimmune (PGA) syndromes. Medicine (Baltimore). 1981;60:355–362. 7. Zlotogora J, Shapiro MS. Polyglandular autoimmune syndrome type I among Iranian Jews. J Med Genet. 1992;29:824–826. 8. Betterle C, Greggio NA, Volpato M. Clinical review 93: autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab. 1998;83:1049–1055. 9. Wolff AS, Erichsen MM, Meager A, et al. Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene. J Clin Endocrinol Metab. 2007;92:595–603. 10. Orlova EM, Bukina AM, Kuznetsova ES, et al. Autoimmune polyglandular syndrome type 1 in Russian patients: clinical variants and autoimmune regulator mutations. Horm Res Paediatr. 2010;73:449–457. 11. Podkrajsek KT, Milenković T, Odink RJ, et al. Detection of a complete autoimmune regulator gene deletion and two additional novel mutations in a cohort of patients with atypical phenotypic variants of autoimmune polyglandular syndrome type 1. Eur J Endocrinol. 2008;159:633–639. 12. Zaidi G, Sahu RP, Zhang L, et al. Two novel AIRE mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) among Indians. Clin Genet. 2009;76:441–448. 13. Mazza C, Buzi F, Ortolani F, et al. Clinical heterogeneity and diagnostic delay of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome. Clin Immunol. 2011;139:6–11. 14. Proust-Lemoine E, Saugier-Véber P, Lefranc D, et al. Autoimmune polyendocrine syndrome type 1 in north-western France: AIRE gene mutation specificities and severe forms needing immunosuppressive therapies. Horm Res Paediatr. 2010;74:275–284. 15. Betterle C, Ghizzoni L, Cassio A, et al. Autoimmunepolyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) in Calabria: clinical, immunological and genetic patterns. J Endocrinol Invest. 2011; DOI: 10.3275/8109. 16. Meloni A, Meloni A, Willcox N, et al. Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients. J Clin Endocrinol Metab. 2012;97:1114–1124. 17. Obermayer-Straub P, Perheentupa J, Braun S, et al. Hepatic autoantigens in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Gastroenterology. 2001;121:668–677. 18. Proust-Lemoine E, Wémeau JL. Apeced syndrome or autoimmune polyendocrine syndrome type 1. Presse Med. 2008;37:1158–1171. 19. Ward L, Paquette J, Seidman E, et al. Severe autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy in an adolescent girl with a novel AIRE mutation: response to immunosuppressive therapy. J Clin Endocrinol Metab. 1999;84:844–852. 20. Ramsey C, Winqvist O, Puhakka L, et al. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum Mol Genet. 2002;11:397–409. r 2013 Lippincott Williams & Wilkins Gastrointestinal Manifestations in APECED Syndrome 21. Eyerich K, Eyerich S, Hiller J, et al. Chronic mucocutaneous candidiasis, from bench to bedside. Eur J Dermatol. 2010;20: 260–265. 22. Conti HR, Shen F, Nayyar N, et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med. 2009;206:299–311. 23. Kisand K, Bøe Wolff AS, Podkrajsek KT, et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med. 2010;207:299–308. 24. Kisand K, Lilic D, Casanova JL, et al. Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur J Immunol. 2011;41:1517–1527. 25. Lilic D, Gravenor I, Robson N, et al. Deregulated production of protective cytokines in response to Candida albicans infection in patients with chronic mucocutaneous candidiasis. Infect Immun. 2003;71:5690–5699. 26. Lilic D, Cant AJ, Abinun M, et al. Chronic mucocutaneous candidiasis. I. Altered antigen-stimulated IL-2, IL-4, IL-6 and nterferon-gamma (IFN-g) production. Clin Exp Immunol. 1996;105:205–212. 27. Rosa DD, Pasqualotto AC, Denning DW. Chronic mucocutaneous candidiasis and oesophageal cancer. Med Mycol. 2008; 46:85–91. 28. Rautemaa R, Hietanen J, Niissalo S, et al. Oral and oesophageal squamous cell carcinoma—a complication or component of autoimmune polyendocrinopathy-candidiasisectodermal dystrophy (APECED, APS-I). Oral Oncol. 2007; 43:607–613. 29. Koch D, Lilic D, Carmichael AJ. Autosomal dominant chronic mucocutaneous candidiasis and primary hypothyroidism complicated by oesophageal carcinoma. Clin Exp Dermatol. 2009;34:e818–e820. 30. Rautemaa R, Richardson M, Pfaller M, et al. Reduction of fluconazole susceptibility of Candida albicans in APECED patients due to long-term use of ketoconazole and miconazole. Scand J Infect Dis. 2008;40:904–907. 31. Siikala E, Richardson M, Pfaller MA, et al. Candida albicans isolates from APECED patients show decreased susceptibility to miconazole. Int J Antimicrob Agents. 2009;34:607–609. 32. Siikala E, Bowyer P, Richardson M, et al. ADH1 expression inversely correlates with CDR1 and CDR2 in Candida albicans from chronic oral candidosis in APECED (APS-I) patients. FEMS Yeast Res. 2011;11:494–498. 33. Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N Engl J Med. 1997;337:1441–1448. 34. Karlsson FA, Burman P, Lööf L, et al. Major parietal cell antigen in autoimmune gastritis with pernicious anemia is the acid-producing H + ,K + -adenosine triphosphatase of the stomach. J Clin Invest. 1988;81:475–479. 35. Toh BH, Gleeson PA, Simpson RJ, et al. The 60- to 90-kDa parietal cell autoantigen associated with autoimmune gastritis is a beta subunit of the gastric H + /K(+)-ATPase (proton pump). Proc Natl Acad Sci U S A. 1990;87:6418–6422. 36. Ekwall O, Hedstrand H, Grimelius L, et al. Identification of tryptophan hydroxylase as an intestinal autoantigen. Lancet. 1998;352:279–283. 37. Oliva-Hemker M, Berkenblit GV, Anhalt GJ, et al. Pernicious anemia and widespread absence of gastrointestinal endocrine cells in a patient with autoimmune polyglandular syndrome type I and malabsorption. J Clin Endocrinol Metab. 2006;91:2833–2838. 38. Uibo R, Krohn K, Villako K, et al. The relationship of parietal cell, gastrin cell, and thyroid autoantibodies to the state of the gastric mucosa in a population sample. Scand J Gastroenterol. 1984;19:1075–1080. 39. Uibo RM, Krohn KJ. Demonstration of gastrin cell autoantibodies in antral gastritis with avidin-biotin complex antibody technique. Clin Exp Immunol. 1984;58:341–347. 40. Camilleri M. Chronic diarrhea: a review on pathophysiology and management for the clinical gastroenterologist. Clin Gastroenterol Hepatol. 2004;2:198–206. www.jcge.com | 119 Kluger et al 41. Juckett G, Trivedi R. Evaluation of chronic diarrhea. Am Fam Physician. 2011;84:1119–1126. 42. Ebert EC. The parathyroids and the gut. J Clin Gastroenterol. 2010;44:479–482. 43. Abboud B, Daher R, Boujaoude J. Digestive manifestations of parathyroid disorders. World J Gastroenterol. 2011;17:4063–4066. 44. Heubi JE, Partin JC, Schubert WK. Hypocalcemia and steatorrhea—clues to etiology. Dig Dis Sci. 1983;28:124–128. 45. Peracchi M, Bardella MT, Conte D. Late-onset idiopathic hypoparathyroidism as a cause of diarrhoea. Eur J Gastroenterol Hepatol. 1998;10:163–165. 46. Högenauer C, Meyer RL, Netto GJ, et al. Malabsorption due to cholecystokinin deficiency in a patient with autoimmune polyglandular syndrome type I. N Engl J Med. 2001;344:270–274. 47. Unsworth DJ, Walker-Smith JA. Autoimmunity in diarrhoeal disease. J Pediatr Gastroenterol Nutr. 1985;4:375–380. 48. Freeman HJ. Adult autoimmune enteropathy. World J Gastroenterol. 2008;14:1156–1158. 49. Montalto M, D’Onofrio F, Santoro L, et al. Autoimmune enteropathy in children and adults. Scand J Gastroenterol. 2009;44:1029–1036. 50. Mais DD, Mulhall BP, Adolphson KR, et al. Thymomaassociated autoimmune enteropathy. A report of two cases. Am J Clin Pathol. 1999;112:810–815. 51. Posovszky C, Lahr G, von Schnurbein J, et al. Loss of enteroendocrine cells in autoimmune-polyendocrine-candidiasisectodermal-dystrophy (APECED) syndrome with gastrointestinal dysfunction. J Clin Endocrinol Metab. 2012;97:E292–E300. 52. Sköldberg F, Portela-Gomes GM, Grimelius L, et al. Histidine decarboxylase, a pyridoxal phosphate-dependent enzyme, is an autoantigen of gastric enterochromaffin-like cells. J Clin Endocrinol Metab. 2003;88:1445–1452. 53. Ohsie S, Gerney G, Gui D, et al. A paucity of colonic enteroendocrine and/or enterochromaffin cells characterizes a subset of patients with chronic unexplained diarrhea/malabsorption. Hum Pathol. 2009;40:1006–1014. 54. Padeh S, Theodor R, Jonas A, et al. Severe malabsorption in autoimmune polyendocrinopathy-candidosis-ectodermal dystrophy syndrome successfully treated with immunosuppression. Arch Dis Child. 1997;76:532–534. 120 | www.jcge.com J Clin Gastroenterol Volume 47, Number 2, February 2013 55. Hori K, Fukuda Y, Tomita T, et al. Intestinal goblet cell autoantibody associated enteropathy. J Clin Pathol. 2003;56: 629–630. 56. Al Khalidi H, Kandel G, Streutker CJ. Enteropathy with loss of enteroendocrine and Paneth cells in a patient with immune dysregulation: a case of adult autoimmune enteropathy. Hum Pathol. 2006;37:373–376. 57. Green PH, Cellier C. Celiac disease. N Engl J Med. 2007;357: 1731–1743. 58. Friedman M, Ramsay DB, Borum ML. An unusual case report of small bowel Candida overgrowth as a cause of diarrhea and review of the literature. Dig Dis Sci. 2007;52:679–680. 59. Scirè G, Magliocca FM, Cianfarani S, et al. Autoimmune polyendocrine candidiasis syndrome with associated chronic diarrhea caused by intestinal infection and pancreas insufficiency. J Pediatr Gastroenterol Nutr. 1991;13:224–227. 60. Domı́nguez-Muñoz JE. Pancreatic exocrine insufficiency: diagnosis and treatment. J Gastroenterol Hepatol. 2011;26(suppl 2):12–16. 61. Hardt PD, Ewald N. Exocrine pancreatic insufficiency in diabetes mellitus: a complication of diabetic neuropathy or a different type of diabetes? Exp Diabetes Res. 2011; 2011:761950. DOI: 10.1155/2011/761950. 62. McMahon FC, Cookson DV, Kabler JD, et al. Idiopathic hypoparathyroidism and idiopathic adrenal cortical insufficiency occurring with cystic fibrosis of the pancreas. Ann Intern Med. 1959;51:371–384. 63. Bereket A, Lowenheim M, Blethen SL, et al. Intestinal lymphangiectasia in a patient with autoimmune polyglandular disease type I and steatorrhea. J Clin Endocrinol Metab. 1995;80:933–935. 64. Makharia GK, Tandon N, Stephen Nde J, et al. Primary intestinal lymphangiectasia as a component of autoimmune polyglandular syndrome type I: a report of 2 cases. Indian J Gastroenterol. 2007;26:293–295. 65. Friedman TC, Thomas PM, Fleisher TA, et al. Frequent occurrence of asplenism and cholelithiasis in patients with autoimmune polyglandular disease type I. Am J Med. 1991;91: 625–630. 66. Järvelä I, Torniainen S, Kolho KL. Molecular genetics of human lactase deficiencies. Ann Med. 2009;41:568–575. r 2013 Lippincott Williams & Wilkins