Gastrointestinal Manifestations in APECED Syndrome

Nicolas Kluger, MD,* Martta Jokinen, MC,* Kai Krohn, MD, PhD,wand Annamari Ranki, MD, PhD*

Abstract: Autoimmune polyendocrinopathy-candidiasis-ectodermaldystrophy (APECED) (or autoimmune polyendocrine syndrometype 1) is a rare autosomal recessive disorder caused by mutations inthe autoimmune regulator gene. It causes a loss in central immunetolerance, failure to eliminate autoreactive T cells in the thymus,and their escape to the periphery. APECED patients are susceptibleto mucocutaneous candidiasis and multiple endocrine and non-endocrine autoimmune diseases. Although it depends on the series,approximately 25% of APECED patients are affected by gastro-intestinal (GI) manifestations, mainly autoimmune-related dis-orders like autoimmune hepatitis, atrophic gastritis with or withoutpernicious anemia (Biermer disease), intestinal infections, andmalabsorption. In contrast to the major organ-specific autoimmunesymptoms of APECED, the GI symptoms and their underlyingpathogenesis are poorly understood. Yet isolated case reports andsmall series depict severe intestinal involvement in children, leadingto malabsorption, multiple deficiencies, growth impairment, andpossible death. Moreover, very few systematic studies of GI func-tion with intestinal biopsies have been performed. GI symptomsmay be the first manifestation of APECED, yet they may havevarious causes; effective treatment will therefore vary. We providehere an updated review of GI manifestations in APECED, includingprinciples of diagnosis and therapy.

Key Words: autoimmune polyendocrinopathy-candidiasis-ecto-

dermal dystrophy, autoimmune polyendocrine syndrome type 1,

gastritis, Biermer disease, hypoparathyroidism, diarrhea, auto-

immune enteropathy

(J Clin Gastroenterol 2013;47:112–120)

Autoimmune polyendocrinopathy-candidiasis-ectodermaldystrophy (APECED, OMIM 240300), also called

autoimmune polyendocrine syndrome type 1, is a rareautosomal recessive disorder caused by mutations in theautoimmune regulator (AIRE) gene located on chromosome21 (21q22.3).1–3 AIRE deficiency causes a loss in centralimmune tolerance, leading to the failure to eliminateautoreactive T cells in the thymus and allowing their escapeto the periphery.3 Because of a founder effect, APECED isparticularly prevalent in Finland (1/25,000)2,4 but isobserved worldwide with variable prevalence.5–16 APECEDpatients are susceptible to mucocutaneous candidiasisand multiple endocrine autoimmune diseases such as

adrenocortical insufficiency (Addison disease), primaryhypoparathyroidism (HP), primary hypogonadism, type Idiabetes, hypothyroidism, and hypophysitis. They may alsodevelop additional nonendocrine autoimmune diseases,such as alopecia areata/totalis, vitiligo, nephritis, and ker-atitis.1 Gastrointestinal (GI) manifestations are included inthe group of “minor” components of APECED and havebeen reported since the 1950s.9 They include mainly auto-immune-related disorders like autoimmune hepatitis,17

atrophic gastritis with or without pernicious anemia (Biermerdisease), intestinal infections, and malabsorption. In contrastto the major organ-specific autoimmune symptoms ofAPECED, the GI symptoms and their underlying patho-genesis are poorly understood. However, clinical studiesestimate the prevalence of GI symptoms and signs (excludinghepatitis) up to roughly 25%, and both cohort and reviewarticles usually describe GI manifestations as “diarrhea,”“constipation,” and “malabsorption.”1,18 Conversely, iso-lated case reports and small series have depicted severeintestinal involvement in children leading to malabsorption,multiple deficiencies, growth impairment,19 and possibledeath.2 Moreover, there are very few systematic studies of GIfunction with intestinal biopsies. GI symptoms may be thefirst manifestation of APECED and the causes may vary;therefore, effective treatment will vary accordingly. We pro-vide here an updated review of GI manifestations inAPECED, including principles of diagnosis and therapy. Allthe GI manifestations are summarized in Tables 1 and 2.

ESOPHAGEAL SYMPTOMS: CANDIDIASIS ANDESOPHAGEAL CARCINOMA

Chronic mucocutaneous candidiasis (CMC) is one ofthe “triad” symptoms characterizing APECED, the othersbeing HP and adrenocortical failure.1–3,5 AlthoughAPECED is one of the primary immunodeficiencies leadingto CMC, it is not the only one.21 Candida infection inAPECED patients affects the nails and the oral, vaginal,and esophageal mucosa.3 Interestingly, patients withAPECED display selective immunodeficiency to Candidabut not to other fungi or bacteria. Systemic disseminationwith potential lethal outcome is possible but quite rare andmostly because of additional iatrogenic factors such asimmunosuppressive therapies.8

Immunity to Candida involves both innate and adap-tive mechanisms; however, an alteration in T-cell cytokinesecretion seems to be crucial for the predisposition. Animpaired Th1 response leads to increased susceptibility tosevere Candida infection,21 and recent studies have shownthat Th17 lymphocytes are essential for Candida resist-ance.22 Th17 lymphocytes secrete interleukin (IL)-17A,IL-17F, IL-21, IL-22, and IL-26, all of which are involvedin recruiting neutrophils and protecting against bacterialand fungal infections.23,24 In CMC, type 1 cytokines[interferon (IFN)g, IL-12, and IL-2] are diminished,

From the *Departments of Dermatology, Allergology and Venereol-ogy, Institute of Clinical Medicine, University of Helsinki, and Skinand Allergy Hospital, Helsinki University Central Hospital; andwClinical Research Institute HUCH Ltd, Helsinki, Finland.

Supported by the European Science Foundation (ESF) and the SigridJuselius foundation.

The authors declare that they have nothing to disclose.Reprints: Nicolas Kluger, MD, Departments of Dermatology, Aller-

gology and Venereology, Skin and Allergy Hospital, HelsinkiUniversity Central Hospital, Meilahdentie 2, P.O. Box 160,Helsinki FI-00029, Finland (e-mail: nicolaskluger@yahoo.fr).

Copyright r 2013 by Lippincott Williams & Wilkins

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whereas type 2 cytokines (IL-4, IL-10) are elevated andwork concurrently to diminish antimicrobial peptideproduction and recruit neutrophils in situ.25,26 Interest-ingly, APECED patients have circulating antibodies againsttype 1 cytokines such as IFN-o and IFN-a (100% and 95%of cases), IL-22 (>90% of cases), and IL-17 (75%).24 Theprevalence, age of presentation, and severity of CMC inAPECED is variable,5,7,16 most likely resulting from dif-ferential mutations of the AIRE gene.24 Overall, IL-17 andIL-22 seem to be key cytokines implicated in the CMC ofAPECED patients. Nevertheless, further studies are war-ranted to clarify whether other components of anti-Candidaimmunity, such as human epithelial defensins, are impairedin APECED.

Oral candidiasis usually presents with pseudomem-branotic lesions, erosion, ulceration, and pain. Candidaesophagitis has been reported to affect 15% to 22% ofAPECED patients,2,24 with pain while swallowing, retro-sternal 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 esophagealcandidiasis.2,16 Chronic inflammation may lead to esoph-ageal stricture,2,5,8,16 which requires treatment with balloondilatation or stenting. Oral and esophageal carcinoma maydevelop over the long term as a complication of chronicinflammation mediated by CMC. Alcohol intake and activesmoking are additional risk factors that may promote car-cinogenesis.27 In the Finnish series of 92 patients, only one40-year-old male patient, with a history of severe chronicoral candidiasis since infancy, smoking, and alcoholdrinking, developed esophageal carcinoma. Dysphagia and

retrosternal pain developed 6 years after the esophagitis,revealing well-differentiated squamous cell carcinomaleading to death 18 months later.28 Of note, esophagealcancer during CMC without APECED has beenreported,27,29 indicating that chronic candidiasis plays arole in carcinogenesis rather than APECED itself.

The management of candidiasis in APECED patients isbased on excellent oral hygiene with careful and regulardental follow-up. Dental plaque should be treated actively, asit may be the source of yeast in the oral cavity. Candidiasisshould be treated aggressively with antimicrobial therapy andregular prophylaxis should be given. Azoles, fluconazoleespecially, are usually recommended as the first-line treat-ment but often lead to selective resistant strains.21,30–32

Therefore, regular fungal sensitivity tests should be per-formed. Topical polyenes (amphotericin B) are preferable, asthey are less prone to selecting resistant Candida strains.28

Echinocandins are available by intravenous infusion butsystemic polyene (amphotericin B) should be restricted tosystemic Candida infection, given its potential side effects.21

Any suspicious lesions, erosion that does not heal, or thick-ening, leukoplakia especially, should be biopsied. Difficultiesin swallowing or eating and retrosternal pain should alsoprompt an esophagoscopic examination.28

GASTRIC SYMPTOMS: CHRONIC GASTRITISAND PERNICIOUS ANEMIA

Chronic atrophic gastritis is an autoimmune diseaseaffecting the gastric parietal cells and intrinsic factor (IF). Iteventually leads to gastric atrophy, which in turn is associatedwith vitamin B12 deficiency and pernicious anemia (PA,Biermer disease).33 The chronic gastritis seen in APECED isof the A type, which, according to the Strickland classi-fication, is based on an autoimmune response to the gastricmucosa. In contrast, the B type of gastritis, thought to beoriginally caused by environmental factors, is in most casesthe consequence of chronic infection withHelicobacter pylori.Patients with A type gastritis have antibodies against thesodium-potassium channel molecule of the parietal cells inthe corpus and fundus of the stomach (parietal cell anti-bodies).34,35 The process starts with superficial gastritis,characterized by lymphocytic infiltration below the epi-thelium that does not reach specific glands. A diffuse gastritisthen follows with lymphocytic infiltration extending to spe-cific glands and to glandular destruction (atrophic gastritis).In the final stage, hydrochloric acid and pepsinogen-pro-ducing cells have disappeared, as has the secretion of gastricIF. PA is thus the end stage of gastric immunologicdestruction, caused not only by the lack of IF, but also byautoantibodies recognizing this vitamin B12-binding proteinand preventing the subsequent translocation of vitamin B12

from the ileum to circulation.33

Chronic gastritis and PA may occur as solitary con-ditions or associated with various autoimmune endo-crinopathies and antireceptor autoimmune diseases.33

These conditions have been reported in approximately 30%of the APECED patients in Finland.2 According to otherseries, the prevalence in APECED patients ranges from 9%to 27%.6–16,36 The circulating antibodies reacting withparietal cells and IF may be detected before any clinicalsymptoms.2 PA usually develops during early adulthood,8

although sometimes in early childhood,37 which differsfrom the solitary PA, usually diagnosed in the sixth dec-ade.33 One reason for the diagnosis at an earlier age may be

TABLE 1. A Review of Gastrointestinal Manifestations DuringAPECED

EsophagusCandida esophagitisEsophageal carcinoma

StomachPernicious anemia (Biermer anemia)Autoimmune gastric atrophyGastric adenocarcinomaGastric carcinoid tumor

BowelPrimary hypoparathyroid-induced hypocalcemiaSecondary hypocalcemia due to malabsorption of vitamin DIntestinal infection: bacterial overgrowth, Candida infection,Giardiasis lamblia, Clostridium difficile

Exocrine pancreatic insufficiency: hypocalcemia, diabetes, celiacdisease, cystic fibrosis, intestinal megaloblastosis due tovitamin B12 deficiency, autoimmune pancreatitis associated ornot to AE*

Autoimmune enteropathyLactase nonpersistance/deficiencyIntestinal lymphangiectasiaCeliac diseaseFunctional disease

Autoimmune hepatitisCholelithiasis

*No case reported in APECED thus far, but considered according to thepancreatitis induced in the knockout Aire� /� mouse model.20

APECED indicates autoimmune polyendocrinopathy-candidiasis-ecto-dermal dystrophy.

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that patients with APECED are closely monitored frominfancy or childhood and are therefore more likely to bediagnosed even before clinical symptoms occur.

Clinical symptoms of the lack of vitamin B12 mayinclude atrophic glossitis with a smooth red beef tongue,diarrhea, and malabsorption if megaloblastosis affects theintestinal epithelial cells.33 Lack of vitamin B12 affects thesynthesis of purines and pyrimidines, leading to deficientDNA synthesis, which results in macrocytosis, anemia,leukopenia, thrombopenia, and pancytopenia. Vitamin B12

deficiency may also cause peripheral neuropathy, degener-ation of the spinal cord, and personality defects. Low serumvitamin B12 associated with parietal cell antibodies andIF antibodies is highly evocative of the diagnosis. How-ever, because APECED patients usually have several

endocrinopathies, their anemia may also be related toAddison disease or hypothyroidism. Therefore, gastricfibroscopy with biopsies remains absolutely mandatory toconfirm the presence of type A chronic gastritis. In general,type A autoimmune gastritis affects only the fundus andcorpus of the stomach, but spares the antrum.33 Theinflammation of the lamina propria eventually leads tointestinal metaplasia that may contribute later to thedevelopment of adenocarcinoma.33 Also, as the antrum isspared in PA, gastrin-producing G cells are stimulated byachlorhydria and the reactive hypergastrinemia leads togastric enteroendocrine cell (EEC) hyperplasia that maylead to the development of carcinoid tumors.33 However, toour knowledge, only Betterle et al8 have reported a case ofgastric adenocarcinoma in an APECED patient. Regular

TABLE 2. Manifestations and Mechanisms of the Main Gastrointestinal Disease of APECED

Symptoms Etiology Antibodies/Targets* Treatment

EsophagusEsophagitis Retrosternal pain,

dysphagiaCandida infection None Antifungal therapy

Esophageal carcinoma Difficulty to eat,vomiting

Chronic inflammation None Surgery, chemotherapy,stenting

StomachPernicious anemia(Biermer anemia)

B12 deficiency Autoimmunity Antibodies against sodium-potassium channel moleculeof the parietal cells and

intrinsic factor

B12 supplementation

Autoimmune gastricatrophy (type A)

None Autoimmunity Antibodies against parietalcell and intrinsic factor

No treatment if no B12

deficiencyGutPrimaryhypoparathyroidism

Chronic diarrhea,hypocalcemia, lowparathormone

Autoimmunity Antibodies against NALP5(NACHT leucine-richrepeat protein 5) and

calcium sensing receptorantibodies

Calcium and vitamin Dsupplementation

Hypocalcemia Chronic diarrhea,hypocalcemia,

normalparathormone

Vitamin D deficiencyrelated to intestinalmalabsorptionw

None Calcium and vitamin Dsupplementation

Intestinal infections Chronic diarrhea Bacterial or parasiticinfestation

None Antibiotics or anti-parasitic treatment

Exocrine pancreaticinsufficiency

Chronic diarrhea Multiple: hypocalcemia,diabetes, celiac disease,

cystic fibrosis, vitamin B12

deficiency (intestinalmegaloblastosis)

Depending on the cause Adapted to the culpritcause

Autoimmuneenteropathy

Chronic diarrhea Autoimmunity Antibodies againsttryptophan hydroxylase and

histidine decarboxylaseTargets: enteroendocrine cells,

Paneth cells, and brushborder cells

Immunosuppressivetherapies in case of severe

symptoms

Lactose intolerance Chronic diarrheaafter milk and dairy

productconsumption

Lactase nonpersistanceor deficiency

None Lactose-free diet

Celiac disease Chronic diarrhea Autoimmunity Antibodies againsttransglutaminase

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.

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intramuscular injections of vitamin B12 every 1 to 3 months isan essential part of APECED treatment.

A rare form of antral gastritis was reported to be linkedto autoantibodies reacting with the gastrin-producing cells inthe antral mucosa.38,39 Oliva-Hemker et al37 observed in ayoung APECED patient mild to moderate chronic inflam-mation on antral biopsies and absence of gastrin secretion.Albeit being a unique case report, it suggests that autoimmuneantral gastritis might be possible in APECED patients.

DIARRHEA, CONSTIPATION, ANDMALABSORPTION

Chronic diarrhea is defined as a decrease in stoolconsistency for >4 weeks and is divided into osmotic,secretory, inflammatory, motility, iatrogenic, and func-tional diseases.40 However, diarrhea is rarely unifactorialand several mechanisms may overlap. Diarrhea in thecontext of malabsorption displays several characteristics:excess gas; weight loss; and fatty-appearing, foul-smelling,light-colored, and greasy, floating or undigested stools thatare difficult to flush. The inflammatory diarrhea in inflam-matory bowel disease or invasive bacterial infections isassociated with blood and pus in the stools.41 Therefore, thefirst step to a precise diagnosis of chronic diarrhea requiresa careful clinical history and examination.40 Interestingly,such precisions on the type of diarrhea are often lacking inthe APECED literature.

Chronic diarrhea is the first manifestation ofAPECED in 5% of patients and severe constipation in2%,2 whereas malabsorption varies from 9% to 26%,according to the series.5,8,9,14 Meloni et al16 recentlyreported that approximately half of their Sardinian patientsshowed periodic intestinal dysfunction. The precise identi-fication of the cause of intestinal symptoms in associationwith APECED, that is, abdominal pain; bloating; andrecurrent, watery or fatty (steatorrhea) diarrhea or con-stipation, is a real challenge for the physician as it is farfrom obvious. Several disorders may co-occur or may fol-low successively over the patient’s lifetime. Therefore, eachnew episode may be related to either a previously identifiedcause or a new one that has not yet been diagnosed.Reports on APECED patient cohorts often lack precisionin this regard, and varying criteria have been chosen todefine GI manifestations. Authors may also evaluate only 1aspect of GI symptoms. For instance, Ahonen et al5

focused only on malabsorption defined as floating stoolsand increased fecal fat excretion. In this case, other causesof diarrhea in APECED patients, as seen above, would bemissed. Often, the precise cause of malabsorption has notbeen fully analyzed5,12 or it may have been multifactorial.14

We next discuss the known causes of GI symptoms inAPECED patients.

Autoimmune HPThe parathyroid glands are involved in calcium regu-

lation through the secretion of parathormone (PTH).Acquired autoimmune HP is one of the cardinal manifes-tations of APECED3,5 and affects approximately 80% ofpatients.2,16 It may start early in life5 and cause hypo-calcemia and hyperphosphatemia. The main GI manifes-tations of HP, irrespective of its cause, are steatorrhea anddiarrhea.42,43 Therefore, diarrhea may be the first symptom

of hypocalcemia and HP in APECED.2,5 Symptoms tend torecur whenever the patient has hypocalcemia1–3; however,not all patients with hypocalcemia develop diarrhea.1

Steatorrhea is due to the insufficient endogenous secretionof cholecystokinin by the duodenal mucosa during a meal.Cholecystokinin stimulates normal gallbladder contractionand pancreatic enzyme secretion.44 Steatorrhea occurs asa consequence of biliopancreatic exocrine deficit. Man-agement includes a medium-chain triglyceride diet andcorrection of HP by administration of vitamin D andnormalization of hypocalcemia.43 A clue for the diagnosisof HP-related steatorrhea is hyperphosphatemia. Hypo-calcemia may also cause watery diarrhea without steator-rhea.45 Therefore, hypocalcemia should be systematicallychecked for any APECED patient with either diarrhea orsteatorrhea.

A minority of APECED patients may not have auto-immune HP. Hypocalcemia then becomes the consequenceand not the cause of steatorrhea. In this case, serum levelsof phosphorus are normal or low because of reactive sec-ondary secretion of PTH.42 Finally, a vicious circle maydevelop: hypocalcemia related to HP is responsible forsteatorrhea, which in turn maintains hypocalcemia bymalabsorption and the absence of PTH secretion.2

Interestingly, the GI manifestations of hypocalcemia donot seem to be well known and may be overlooked, asillustrated by the case of a man with a long history ofAPECED and HP, who developed diarrhea and steatorrheaat the age of 34 years. It was then revealed that the episodesoccurred in association with hypocalcemia.46 The authorsfurther reported that staining of chromogranin and chol-ecystokinin from the duodenum were negative but no circu-lating antibodies against EECs or cholecystokinin-producingcells were found. Cholecystokinin immunopositivity andsecretion were reversed with a medium-chain triglyceride diet.The authors hypothesized various underlying mechanismsbut did not consider hypocalcemia as a cause of mal-absorption. It may be speculated that the hypocalcemia, inrelation to the HP, was mainly responsible for the diarrhea,which improved by oral calcium intake and the medium-chain triglyceride diet. The absence of EECs as a result ofautoimmune enteropathy (AE) may also have played a role.

AEAE, first described in 1982, is a rare autoimmune disorder

affecting mainly children. It is characterized by: (i) protracteddiarrhea and severe enteropathy with small-intestinal villousatrophy; (ii) no response to exclusion diets; (iii) evidence of apredisposition to autoimmune disease (circulating enterocyteantibodies or associated autoimmune diseases); and (iv) nosevere immunodeficiency.47–49 Autoantibodies against intesti-nal brush border, enterocyte cytoplasm, goblet cells, and a75-kDa antigen located in the gut and kidney (AE 75) aredetected in association with AE.49 Moreover, AE is one of themain features of immune dysfunction, polyendocrinopathy,enteropathy, and X-linked syndrome due to mutation in theFOXP3 gene on the X chromosome. The FOXP3 mutationleads to a loss of function of CD4+ CD25+ T-regulatorycells, which are implicated in the maintenance of self-tolerance.Interestingly, APECED and X-linked syndrome are bothpolyglandular syndromes with immune deficiencies, despitedifferent clinical presentations.4 Finally, thymoma, whichclosely resembles APECED in some aspects,24 has beenreported to be associated with AE in rare cases.50 InAPECED, AIRE deficiency is responsible for the loss of

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tolerance and autoreactive T cells may escape to the periph-ery.4 Therefore, it is highly probable that some autoreactivecirculating clones can be directed toward intestinalcomponents.

Ekwall et al36 identified tryptophane hydroxylase(TPH) as an intestinal autoantigen in APECED patients.TPH is expressed in serotonin-producing cells in the centralnervous system and intestine. In their series of 80 patients,they were able to relate “GI symptoms” to the presence ofcirculating TPH antibodies and also to the total absence ofenterochromaffin 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. Theyplay a key role in gut growth, blood flow, motility, and thesecretion of pancreatic enzymes, bile and bicarbonate-richfluid.51 TPH antibodies were detected in 89% of APECEDpatients with GI symptoms and in 34% of those without.36

Posovszky et al51 found TPH antibody positivity in 3 oftheir 4 patients with GI symptoms. TPH antibodies some-times preceded clinical symptoms.36 Conversely, TPHautoantibodies are absent in other inflammatory or auto-immune intestinal diseases such as Crohn’s disease, celiacdisease, or AE. In addition, Skoldberg et al52 identifiedautoantibodies against histidine decarboxylase expressed byEEC-like cells in the gastric mucosa. It should be noted thatEEC staining of intestinal biopsies is not a routine proce-dure in cases of diarrhea or malabsorption, as stressed byOhsie et al.53

In some cases, GI symptoms are the first or among thefirst symptoms of APECED.37,51 According to Ahonenet al, 10% of APECED patients present with GI manifes-tations that then reveal more severe disease.5 Posovszkyet al noted that EECs were either initially absent or grad-ually lost during follow-up in their small series of patientswith APECED.51 Several other small series and case reportsof APECED patients with GI manifestations have con-firmed the absence of EECs along the GI tract with lack ofchromogranin A, serotonin, and Grimelius silver staining(Fig. 1).14,19,37,46,51–54 Notably, EECs are not affected inother intestinal diseases with autoimmune background.Oliva-Hemker et al37 and Padeh et al54 found antibodiesagainst EECs and brush borders, respectively, in theirpatient sera. Paradoxically, the lack of EECs is the main,and if not only, histologic abnormality in the intestines ofAPECED patients as routine histopathologic analyses shownormal-appearing mucosa, absence of villous atrophy andlack of inflammation in the intestinal mucosa.37,51,53

Nevertheless, some authors observed the presence of a mildto moderate unspecific inflammatory infiltrate in the GImucosa supporting an autoimmune origin.19,37,51 Besides,the efficacy of immunosuppressive therapy on the course ofGI symptoms is variable.14,19,51,54 Proust-Lemoine et al14

reported that EECs could be found again under immuno-suppressive treatment, but the potential reversibility ofEECs may be independent of the treatment, according tosome authors.46,51 It should nevertheless be stressed thatAE affects mainly children rather than adults. Symptomsare prominent and severe during early childhood and mayimpair growth.19 It is not clear to what extent AE is similarin adult APECED patients. The existence of AE itself as adistinct entity in adults is also debated.48

Intestinal autoimmunity is only directed toward EECswith a mild inflammatory infiltrate (when seen) inAPECED, whereas childhood AE shows aspects close toceliac disease with total villous atrophy, crypt hyperplasia,

dense lymphoplasmacytic infiltrate into the lamina propriaand sometimes crypt abscesses.49 Gastritis is also observedduring AE.48,49 Oliva-Hemker et al37 have emphasized thepathologic differences between primary PA and atrophicgastritis in APECED. The possibility of variant forms ofAE has recently been stressed.55,56 Al Khalidi et al56

reported the case of a 21-year-old male patient who pre-sented not only villous atrophy and chronic inflammationbut 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 AEdirected strictly against EECs. This type shows clearlydistinctive features compared with the “classic” childhoodAE and should prompt confirmation by EEC staining andimmunosuppressive therapies if necessary.

Celiac DiseaseCeliac disease is an autoimmune disorder affecting

approximately 1% of the adults and children in the generalpopulation.57 Screening for celiac disease is prompted byunexplained bloating or abdominal distress, chronic diar-rhea with or without malabsorption, irritable bowel syn-drome, and abnormalities on laboratory tests indicatingpossible malabsorption. However, celiac disease remainsextremely rare in APECED. To date, only Betterle et al8

have reported 2 cases, which represented only 5% of thepatients in their series. None of the Finnish APECEDpatients in our experience has developed this disease. It thusremains unclear whether this association is fortuitous ornot. However, we suggest looking systematically for celiacdisease during the exploration of an APECED patient withchronic intestinal symptoms.

Intestinal InfectionsIntestinal candidiasis may also be responsible for

watery diarrhea and malabsorption.21 As with esophagitis,intestinal infection can occur without concomitant oralcandidiasis.2 In their French series of 19 patients, Proust-Lemoine et al14 found 3 patients (26%) in whom mal-absorption improved after antifungal therapy. Besides, oneof their young patients had esophageal and colonic candi-diasis on fibroscopy and colonoscopy, respectively.14

In cases of abdominal symptoms potentially related toCandidiasis, feces and small bowel aspirates should beexamined for intestinal Candida infestation.58 Oral anti-fungal medications are not always efficient and intravenoustherapy may be needed.2 Perheentupa reported the case of a30-year-old patient with no ascertained deep infection ofCandida but who was found at autopsy to have Candidaabscesses of the pericardium and small intestine withnecrotizing inflammation of the colon and mesenterium.2

The bacterial and parasitic infections that maycause diarrhea include bacterial overgrowth,19 Clostridiumdifficile2 and Giardiasis59 (Fig. 3). Of note, a 19-year-oldfemale patient died from Campylobacter sepsis in severecoprostasis.2

Pancreatic Exocrine Insufficiency (PEI)PEI typically manifests with steatorrhea and malnu-

trition. Causes include loss of pancreatic parenchyma(chronic pancreatitis, cystic fibrosis), tumoral pancreaticduct obstruction, decreased pancreatic stimulation (celiac

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FIGURE 1. Immunohistochemistry of colon samples with chromogranin A and serotonin stainings. A, Normal staining of enter-oendocrine cells in the colon (chromogranin A staining �10). B, Complete absence of straining of chromogranin A staining (�10) inthe colon of a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). C, Normal staining ofenteroendocrine cells in the colon (serotonin staining, �10). D, Complete absence of straining of serotonin staining (�10) in the colonof a patient with APECED (serotonin staining, �10).

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disease, HP), acid-mediated inactivation of pancreaticenzymes, and GI and pancreatic surgical resections.60 PEIwas reported in 4% (5/91) of the Finnish series of APECEDpatients,2 including 1 patient with defective bile acid reab-sorption (1%).13 A few isolated cases have been reported,as well.19,51,54,59 The diagnosis of fat malabsorption is basedon the quantification of a fat absorption coefficient afterfecal fat determination after 3 days of stool collection.60

Fecal elastase-1 concentration has also proven to be avaluable indirect and noninvasive method for detectingPEI.61 However, various disorders may be responsible forPEI in APECED: hypocalcemia, diabetes19,59—as diabeteshas been discussed as a cause of PEI61—and even celiacdisease or cystic fibrosis. Therefore, once PEI has beendiagnosed, the cause of this deficiency must be determined.Interestingly, Ramsey et al20 observed no microscopicanomaly in the pancreas of their knockout Aire� /� mice,but 47% of the mouse sera contained autoantibodiesagainst the exocrine pancreas. Therefore, the possibility ofgenuine autoimmunity against the exocrine pancreasremains a possibility. To the best of our knowledge, no caseof autoimmune pancreatitis associated with APECED hasever been reported in humans.

Therapy is based on oral intake of exogenous pan-creatic enzymes,59 irrespective of the degree of steatorrhea

and the presence of other symptoms, and diet modification(smaller meals, avoidance of food difficult to digest, fat-soluble vitamin intake).60

MiscellaneousVarious other conditions have been described anec-

dotally. Without the systematic exploration of APECEDpatients, it is currently unknown whether the followingassociations are fortuitous or not: cystic fibrosis of thepancreas,62 intestinal lymphangiectasias,14,63,64 and chol-elithiasis.8,65 To our knowledge, Ward et al19 reported theonly case of hypolactasia, in a 13-year-old girl. However,she also showed bacterial overgrowth and exocrine pan-creatic deficiency19 and a lactose-free diet was ineffective.Lactase nonpersistence (adult-type hypolactasia) and lac-tase deficiency may be confounding factors.66 Finally,despite its fortuitous association with APECED, irritablecolon syndrome is sufficiently frequent to justify adding itto the list of differential diagnoses of GI symptoms inAPECED patients.

CONCLUSIONSGI manifestations have been suggested as a “minor”

component of APECED, but they are far from insignif-icant. In our experience, patients often fail to specificallymention these symptoms and hence they are usually over-looked in the midst of the many signs and symptoms thatneed to be managed.

Difficulties in diagnosis often occur because patientsmay develop different disorders showing similar symptoms.Moreover, the disorders may be concurrent or occur suc-cessively over the patient’s lifetime. Hypocalcemia is thefirst abnormality that should be screened for and managedin the case of malabsorption in an APECED patient. Ifthere is no hypocalcemia, nor improvement despite efficientmanagement of HP, further explorations are warranted.Autoimmunity should be suspected when anti-infectiousagents, normocalcemia, and pancreatic supplementationtablets have not improved the symptoms. EEC immunos-taining should be systematically performed wheneverintestinal biopsies are obtained in a patient diagnosed withor suspected of having APECED. Overall, the gastro-entererologist should be intimately involved in the multi-disciplinary care of APECED patients.

FIGURE 2. Candida infection during esophagitis in an auto-immune polyendocrinopathy-candidiasis-ectodermal dystrophypatient (Periodic Acid Schiff staining, �20).

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).

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