Download Gastrointestinal Manifestations in APECED Syndrome

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
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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,
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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
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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
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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
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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
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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
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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
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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,
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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
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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).
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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).
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Volume 47, Number 2, February 2013
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