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SZKOLENIE PODYPLOMOWE/POSTGRADUATE EDUCATION
Endokrynologia Polska/Polish Journal of Endocrinology
Tom/Volume 63; Numer/Number 3/2012
ISSN 0423–104X
Piotr Miśkiewicz MD, PhD, Department of Internal Medicine and Endocrinology, Medical University of Warsaw, ul. Żwirki i Wigury 61,
02–001 Warszawa, Poland, e-mail: p.miskiewicz@wp.pl
Coeliac disease in endocrine diseases of autoimmune origin
Celiakia w chorobach endokrynologicznych pochodzenia autoimmunologicznego
Piotr Miśkiewicz1, Anna Kępczyńska-Nyk1, Tomasz Bednarczuk1, 2
1Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw
2Endocrinology Unit, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw
Abstract
Coeliac disease (CD, sometimes called gluten-sensitive enteropathy or nontropical sprue) is an inflammatory disorder of the small intestine
of autoimmune origin. It occurs in genetically predisposed people and is induced by a gluten protein, which is a component of wheat.
The prevalence of histologically confirmed CD is estimated in screening studies of adults in the United States and Europe to be between
0.2% and 1.0%. The results of previous studies have indicated that the prevalence of CD is increased in patients with other autoimmune
disorders such as: autoimmune thyroid diseases, type 1 diabetes mellitus, and Addison’s disease. A coincidence of the above diseases
constitutes autoimmune polyglandular syndrome (APS). The high prevalence of CD in APS is probably due to the common genetic
predisposition to the coexistent autoimmune diseases. The majority of adult patients have the atypical or silent type of the disease. This
is the main reason why CD so often goes undiagnosed or the diagnosis is delayed. CD, if undiagnosed and untreated, is associated with
many medical disorders including haematological (anaemia), metabolical (osteopenia/osteoporosis), obstetric-gynaecological (infertil-
ity, spontaneous abortions, late puberty, early menopause), neurological (migraine, ataxia, epilepsy) as well as with an increased risk of
malignancy, especially: enteropathy-associated T-cell lymphoma, small intestine adenocarcinoma, and oesophageal and oropharyngeal
carcinomas. Early introduction of a gluten-free diet and lifelong adherence to this treatment decreases the risk of these complications. (Pol
J Endocrinol 2012; 63 (3): 240–249)
Key words: coeliac disease, autoimmune polyglandular syndrome, Graves’ disease, autoimmune thyroid disease, type 1 diabetes, autoimmune
adrenal insufficiency
Streszczenie
Celiakia (inaczej: glutenozależna choroba trzewna, enteropatia glutenowrażliwa, sprue nietropikalna) jest enteropatią zap al ną jelita cienkiego
o podłożu autoimmunologicznym, spowodowaną trw ałą ni eto ler anc ją gl ute nu z aw art ego w zb ożach, występującą u os ób z pre dys poz ycj ą
genetyczną. Częstość potwierdzonej histopatologicznie celiakii w ogólnej populacji dorosłych, według wyników badań przesiewowych
przeprowadzonych w Europie oraz Stanach Zjednoczonych, wynosi 0,2–1,0%. Wyniki dotychczasowych badań suge ru ją, że ryzyko zachoro-
wania na celiakię je st k ilk akr ot nie większe u pacjentów z innymi chorobami autoimmunologicznymi, jak np.: choroby autoimmunologiczne
tarczycy (AITD), cukrzyca typu 1 (T1D) czy choroba Addisona. Powyższe choroby wchodzą w skład autoimmunologicznych zespołów
niedoczynności wielogruczołowej (APS). Jedną z p rzy czy n wi ększej częstości występowania celiakii w APS, w porównaniu z ogólną pop u-
lacją, jest prawdopodobnie wspólna predyspozycja genetyczna. U osób dorosłych zdecydowaną większość p rzy pad ków sta now ią postacie
atypowe i nieme. Wpływa to na opóźnioną i obniżoną wykrywalność choroby. Nierozpoznana i nieleczona celiakia może prowadzić do
wielu zaburzeń, w tym m.in.: hematologicznych (niedokrwistość), metabolicznych (osteopenia/osteoporoza), ginekologiczno-położniczych
(niepłodność, wzrost częstości samoistnych poronień, opóźnione dojrzewanie i wcześniejsza menopauza) i neurologicznych (migrena,
ataksja, padaczka). Nieleczona celiakia zwiększa również ogólne ryzyko zachorowania na złośliwe nowotwory, w tym przede wszystkim
na: chłoniaka jelita cienkiego, gruczolakoraka jelita cienkiego, gardła i przełyku. Skuteczne leczenie (dieta bezglutenowa), wprowadzone
wcześnie i kontynuowane przez całe życie, zmniejsza ryzyko wystąpienia wymienionych powikłań. (En dok ry nol Pol 2 012 ; 63 (3) : 24 0– 249 )
Słowa kluczowe: choroba trzewna, autoimmunologiczny zespół niedoczynności wielogruczołowej, choroba Gravesa i Basedowa,
autoimmunologiczna choroba tarczycy, cukrzyca typu 1, autoimmunologiczna niedoczynność nadnerczy
Case report
A 22 year-old female was admitted to the clinic for her
regular check-up. She had been diagnosed with Graves’
disease (GD) at the age of 15. She was treated with an-
tithyroid drugs from the age of 15 to the age of 20 and
twice underwent treatment with radioiodine (at the
age of 20). Before admission to hospital, she had been
taking 150 µg of levothyroxine. She was suffering from
recurrent constipation and moderate abdominal pain.
Additionally, she complained of a feeling of enamel
oversensitivity and severe migraines, which required
treatment with non-steroidal anti-inflammatory
drugs. For several years, the patient was diagnosed
with an iron deficiency and administered iron orally.
She denied having heavy menorrhagia. She pointed out
that the presence of autoimmune disorders ran in her
family (her father suffered from GD as well). Laboratory
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SZKOLENIE
PODYPLOMOWE
tests showed a normal TSH serum level (1.07 uIU/mL,
N: 0.2–4.0) a low ferritin level (6 ng/mL, N: 13–150),
a low iron level (36 ug/ml, N: 37–181), normal serum
Hb, folic acid, vitamin B12, calcium, phosphorus, total
proteins and albumin levels. Specific serological stud-
ies were performed revealing high levels of IgA tissue
transglutaminase antibodies (IgA TTG) (178.1 U/mL;
N: < 20.0) and IgA endomysial antibodies (IgA EMA)
(54.5 U/mL; N: < 20.0). An endoscopy of the upper di-
gestive tract was performed and a biopsy was obtained
from the descending part of the duodenum. Duodenal
mucosa showed atrophic changes with loss of folds
and contained visible fissures. Microscopic examina-
tion showed an increase in intraepithelial lymphocytes,
crypt hyperplasia and villous atrophy — Type III in
Marsh classification (Tab. I, Fig. 1). Coeliac disease (CD)
was diagnosed and a gluten-free diet was introduced.
The patient was invited for a check-up three months
after the introduction of a gluten-free diet, and neither
symptoms of digestive system disorders, nor migraines
and enamel oversensitivity were present. However, it
was observed that serum iron and ferritin concentra-
tions remained low. During following check-ups, the
dose of levothyroxine was gradually lowered to 125 µg,
with a normal serum TSH level. Iron supplements were
stopped and gradually blood iron and ferritin levels
stabilised. The patient regularly visits an endocrinologist
and a gastroenterologist.
Introduction
Coeliac disease (CD), also known as gluten-sensitive
enteropathy and nontropical sprue,, is a small bowel
disorder characterised by mucosal inflammation of
autoimmune origin caused by persistent intolerance to
gluten, a protein which is a component of cereal (rye,
wheat, barley). CD occurs in people with a genetic pre-
disposition [1]. The symptoms of CD were first described
by Dr. Samuel Gee in 1888, but the aetiology of the
symptoms remained unclear for many years [2]. In the
1940s, a paediatrician from Denmark, Wiliam K. Dicke,
recognised the association between diets which con-
tained gluten and the symptoms of CD [3]. In periods
of food shortages during the Second World War, there
were areas where people were poorly nourished and
where bread was replaced by a non-cereal substitute.
Dicke observed a recurrence of symptoms when bread
was reintroduced after the war. Initially, CD was consid-
ered to be a childhood disease, and the frequency of the
disease was estimated at about 1:4,000. After introducing
new, more sensitive and more specific diagnostic tests,
the recognisability of CD markedly increased. CD was
more and more frequently diagnosed in adults. Further
investigations revealed that the prevalence of CD is
more often seen in patients with other autoimmune
disorders such as autoimmune thyroid disease (AITD)
[4–13], type 1 diabetes (T1DM) [14–16], and Addison’s
disease [17–20]. The above-mentioned autoimmune
I II IIIa IIIb IIIc
Figure 1. Extent of small intestinal mucosal changes according to the Marsh histological damage score; the figure shows spectrum of
changes in mucosa of small intestine according to the Marsh classification and AGA. Histologically confirmed coeliac disease can be
diagnosed in cases IIIa, IIIb, IIIc (villous atrophy at different degree) [34]
Ryc ina 1 . Schemat przedstawiający zakres zmian błony śluzowej jelita cienkiego zgodnie z klasyfikacją Marsh; na rycinie przedstawiono
zakres zmian w obrębie błony śluzowej jelita cienkiego zgodnie z klasyfikacją Marsh i kryteriami Amerykańskiego Towarzystwa
Gastroenterologicznego. Histopatologicznie potwierdzoną celiakię można rozpoznać w przypadku zmian IIIa, IIIb, IIIc (zanik kosmków
o różnym stopniu zaawansowania) [34]
Table I. Histologic grading in coeliac disease (Marsh) [34]
Tabela I. Klasyfikacja zmian histopatologicznych w celiakii
(Marsh) [34]
Classification Description
Marsh 0 No changes in mucosal and villous architecture
Marsh I Normal mucosal and villous architecture
Increased numbers of intraepithelial
lymphocytes
Marsh II Similar to Marsh I but with enlarged crypts
(hyperplastic)
Marsh IIIa Partial villous atrophy
Marsh IIIb Subtotal villous atrophy
Marsh IIIc Total villous atrophy
Marsh IV Total villous atrophy and hypoplastic crypts
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Coeliac disease and other autoimmune disorders Piotr Miśkiewicz et al.
SZKOLENIE
PODYPLOMOWE
diseases are part of the autoimmune polyglandular
syndrome (APS). The coexistence of autoimmune
diseases is probably connected to a common genetic
predisposition.
Epidemiology
The prevalence of histologically confirmed CD in the
general adult population in relation to screening re-
search from Europe (Italy, Holland, Germany, Great
Britain, Iceland, Greece) and the United States has
been estimated to be between 0.2 and 1.0% [21–27]
(Tab. II). The data concerning CD in Poland regards
mainly children and is based on classical symptoms
of the disease, which is the reason for underdiagnosis
(most research was performed in the 1980s and 1990s)
[28–33]. There have been no screening studies evaluat-
ing the frequency of CD in adults in Poland.
Clinical manifestations and types
of coeliac disease
Clinical symptoms of CD are characterised by a wide
spectrum within the clinical picture. In younger patients
(infants, young children), we often encounter the classi-
cal type of CD (chronic diarrhoea with hypoalbuminae-
mia, electrolyte abnormalities, abdominal pain) (Tab. III).
Diarrhoea occurs significantly less often in older chil-
dren and adults. Complaints in these groups are often
non-specific and less intensive (flatulence, temporary
abdominal pain) or even absent [34]. These are so called
atypical or silent types of the disease, which are difficult
to diagnose. Symptoms may actually concern all systems
within the human body (Tab. IV). With latent types of
CD in patients with genetic predispositions (genotype
HLA-DQ2 or DQ8), elevated IgA TTG and/or IgA EMA
levels are to be found and minimal changes (increased
intraepithelial lymphocytes of the intestine) or lack of
any histological changes can be seen in tissue samples
taken from the distal part of the duodenum. In order
to describe the variability of CD, it is often compared to
an iceberg. The tip above the water represents patients
with classical symptoms, but the greater part, which
is hidden, consists of asymptomatic patients or those
with atypical symptoms [35, 36] (Fig. 2). There are no
clearly marked borders between the different types of
CD because of its numerous clinical symptoms, and its
histological and immunological picture.
Table II. Prevalence of coeliac disease in different populations of healthy individuals
Ta b e l a I I . Badania przedstawiające częstość wys tępowania choroby trzewnej w różnych populacjach zdrowych dorosłych osób
Study Population Size of the study group (n) Coeliac disease [%]
Rostami et al., 1999 [25] Holland 1,000 0.3%
Volta et al., 2001 [27] Italy 3,483 0.5%
Henker an et al., 2002 [22] Germany 4,313 0.2%
Fasano et al., 2003 [21] USA 2,848 1.0%#
Sanders an et al., 2003 [26] UK 1,200 1.0%
Roka et al., 2007 [24] Greece 2,230 0.2%
Johannsson et al., 2008 [23] Island 813 0.7%
Population — group of individuals on whom the study was performed; the study group — number of individuals who underwent serologic tests specific
for coeliac disease; coeliac disease (%) — prevalence (%) of histologically confirmed coeliac disease in investigated population; #in Fasano’s study only
serological tests were estimated (only 20% of individuals underwent endoscopy and histological evaluation)
Table III. Types of coeliac disease [1, 34]
Tabela III. Kliniczne postacie celiakii [1, 34]
Types of coeliac disease Clinical symptoms Serological evaluation:
IgA EMA/IgA TTG
Histological evaluation
of small bowel biopsy
Classic disease Symptoms of malabsorption + +
Atypical/poor symptomatic Minor gastrointestinal complaints or other symptoms + +
Asymptomatic/silent No symptoms + +
Latent/potential No symptoms + –
Serological evaluation: IgA EMA/IgA TTG (+) — elevated IgA endomysial antibodies and/or IgA tissue transglutaminase antibodies; histological
evaluation of the small intestine (+) — at least partial villous atrophy — Marsh III; (–) — no villous atrophy in histological examination
243
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Diagnosis of coeliac disease
Diagnosis of CD is based on serological tests and his-
tological evaluation of a small bowel biopsy. In some
doubtful situations, genetic tests can be performed
(CD occurs in genetically predisposed individuals with
HLA-DQ2 and/or DQ8). An approach to the diagnosis
of CD is summarised in Figure 3.
Serological evaluations
All diagnostic tests should be performed during
a gluten-rich diet. Nowadays, there are two tests of
high sensitivity and specificity: IgA TTG and IgA EMA,
which have equivalent diagnostic accuracy (Tab. V). IgA
EMA was discovered by a Polish scientist, Professor
Tadeusz Chorzelski, in 1983 [37]. Performing both of
these tests improves sensitivity by almost 100%. Due to
easier ambulatory procedures (ELISA, enzyme-linked
immunosorbent assays), some scientists recommend us-
ing the IgA TTG test first (the IgA EMA test is frequently
performed by a time-consuming indirect immunofluo-
rescence method). It is not advisable to use other serum
antibodies’ assays (antigliadin, antireticuline). Some
scientists recommend an evaluation of serum total anti
IgA level, and when the result is negative, tests for IgG
EMA and/or IgG TTG are recommended.
Histopathological examination
Patients positive with IgA EMA or IgA TTG should
undergo endoscopy of the upper digestive tract with
a small bowel biopsy (4–6 biopsies from the distal part
of the duodenum). A wide spectrum of histological
changes, ranging from increased intraepithelial lympho-
cytes to flat mucosal atrophy, contribute to histological
changes in CD, which can be described using the Marsh
classification (Tab. I) [34]. Diagnosis of CD is established
in patients who have at least partial villous atrophy
(Fig. 1). To avoid false diagnosis, the histological evalu-
ation should be performed in reference clinics.
Genetic evaluations
Antigen HLA-DQ2 is confirmed in 90–95%, and an-
tigen DQ8 in 5–10%, of patients with CD [38]. The
presence of HLA-DQ2 and/or DQ8 is necessary for the
development of symptoms of CD. However, genetic
evaluations are very rarely performed, and they are
restricted to situations in which other methods have
failed. A negative result of genetic evaluation excludes
a diagnosis of CD.
Table IV. Clinical symptoms of coeliac disease
Tabela IV. Objawy kliniczne celiakii
Organ abnormalities Symptoms
Digestive system Diarrhoea, constipation, distension, abdominal pain
Nervous system Ataxia, polyneuropathy, migraines, epilepsy
Reproductive disorders Women: delayed menarche, early menopause, higher rates of miscarriage, low birth weight
Men: hypogonadism, sexual dysfunction, low sperm quality
Haematological disorders Iron deficiency, vitamin B12 deficiency, folic acid deficiency, anaemia
Metabolic disorders Osteopenia, osteoporosis
Dermatologic disorders Dermatitis herpetiformis
Neoplasms Enteropathy-associated T-cell lymphoma-EATL, adenocarcinoma of small bowel, oropharynx and
oesophagus
Others Elevated transaminase levels, prevalence to liver diseases (like primary sclerosing cholangitis,
nonalcoholic fatty liver disease, liver cirrhosis and primary biliary cirrhosis), IgA deficiency, dental-enamel
hypoplasia, hyposplenism, psychiatric disorders
Figure 2. Iceberg showing wide spectrum of clinical symptoms
of coeliac disease (modified according to [35])
Rycina 2. Góra lodowa przedstawiająca spektrum objawów
klinicznych celiakii (zmodyfikowano na podstawie [35])
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Coeliac disease and other autoimmune disorders Piotr Miśkiewicz et al.
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Coeliac disease and autoimmune diseases
Previous studies have shown that patients suffering
from autoimmune diseases are more predisposed to CD
compared to the general population. Examples of auto-
immune diseases are: T1DM, AITD, and Addison’s dise-
ase. The frequency of autoimmune diseases associated
with CD is depicted in Table VI. Simultaneously, judg-
ing from other studies of patients with CD, it may be
stated that the frequency of other autoimmune diseases
in patients with CD is also above normal compared to
a healthy population. Therefore, in all cases regarding
patients with autoimmune disease and suspected of suf-
fering from CD, a proper diagnostic evaluation should
be performed. This often leads to the diagnosis of pa-
tients with CD of non-typical symptoms. The diagnosis
of CD and initiation of the correct therapy (gluten-free
diet) can prevent patients from suffering from many
disorders. Additionally, effective therapy can influence
the course and treatment of other autoimmune diseases
Figure 3. The diagnostic approach to coeliac disease (adapted from [70], up to date 19.2); *moderate or high probability: family history,
iron-deficiency anaemia of unknown origin, diarrhoea, failure to thrive in children, type 1 diabetes; IgA TTG: IgA tissue transglutaminase
antibodies; IgA EMA: IgA antiendomysial antibodies; antibodies: IgA EMA and/or IgA TTG; Consider 1: repeat IgA TTG, repeat biopsy
in reference clinic, multiply biopsy, histological evaluation by another pathologist, review adherence to gluten free diet; Consider 2: total
IgA measurement, perform genetic tests (HLA DQ2, -DQ8), consider other than coeliac disease causes of villous atrophy (cow milk
or other proteins intolerance, giardiasis, eosinophilic gastroenteritis, duodenitis, intestinal ischaemia, intestinal lymphoma, Crohn’s
disease, severe malnutrition)
Rycina 3. Schemat diagnostyczny celiakii (opracowano na podstawie [70], uptodate 19.2); *ryzyko średnie i duże: obciążający wywiad
rodzinny w kierunku celiakii, niedokrwistość z niedoboru żelaza o niejasnej etiologii, biegunka tłuszczowa, opóźnione wzrastanie
u dzieci, cukrzyca typu 1; IgA TTG — przeciwciała przeciwko tkankowej transglutaminazie w klasie IgA; IgA EMA — przeciwciała
przeciwendomyzjalne w klasie IgA; przeciwciała: IgA EMA i/lub IgA TTG: Rozważ 1: powtórzenie IgA TTG, powtórzenie biopsji
w referencyjnym ośrodku, wykonanie większej liczby wycinków, ocena wycinków przez drugiego histopatologa, sprawdzenie czy pacjent
przyjmował re gul arn ą die tę; Rozważ 2: p omi ar s tężenie całkowitego IgA, wykonanie badania genetycznego HLA DQ2, -DQ8, rozważenie
innej przyczyny atrofii kosmków (nietolerancja mleka krowiego oraz innych białek, giardioza, eozynofilowe zapalenie błony śluzowej
żołądka i jelit, zapalenie błony śluzowej dwunastnicy, niedokrwienie jelit, chłoniak jelita cienkiego, choroba Leśniowskiego-Crohna,
ciężkie niedożywienie)
Table V. Sensitivity and specificity of serological tests in diagnostics of coeliac disease (adapted from [34])
Tabela V. Czułość i specyficzność badań serologicznych w diagnostyce celakii (zmodyfikowano na podstawie [34])
Antibodies Sensitivity 95% Cl Specificity 95% Cl
IgA TTG 95.1% 91.8–98.1 98.3% 97.1–99.6%
IgA EMA 90.2% 86.3–92.5% 99.6% 98.4–99.9%
IgA TTG — IgA tissue transglutaminase antibodies; IgA EMA — IgA endomysial antibodies; CI — confidence interval
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which accompany CD (for example lowering doses of
levothyroxine in patients with hypothyroidism, and
lowering doses of hydrocortisone in patients with pri-
mary adrenal insufficiency).
Pathogenesis of the coincidence of coeliac disease
and other autoimmune diseases
CD can appear separately or be a part of APS. Ac-
cording to the definition, APS is a group of diseases
of autoimmune origin characterised by hypofunction
of a couple of endocrine glands [39, 40]. A common
genetic origin is the reason that a patient with one
autoimmune disease is more predisposed to other
autoimmune diseases. The occurrence of the symp-
toms of these diseases is usually not synchronised
in time. A patient diagnosed with one autoimmune
disease often shows a positive result with antibod-
ies characterised for another autoimmune disease,
although without yet displaying clinical symptoms or
organ failure. This can be called potential or silent APS
[41]. An example of this kind of syndrome is the state-
ment of presence of antibodies specific for CD (e.g.
IgA TTG), without any specific histological changes
in a patient with another autoimmune disorder (e.g.
GD). More detailed research, for example by using
an electron microscope, can confirm microvillous
atrophy in some of these patients [42]. It is confirmed
that some patients will develop the full histological
features of CD in the future.
We can define different types of APS, which depends
on the associated conditions of the diseases. Enthusiasts
of narrow classification classify APS into two groups
[43], while others classify APS into three [40] or even
four groups [44] (Tab. VII).
APS types are distinguished according to different
modes of inheritance. APS 1 is rare, usually appears
in childhood, is monogenic, and is connected to mu-
tations in an autoimmune-suppressor gene (AIRE,
autoimmune regulator). It is defined by the presence
of hypoparathyroidism, adrenal insufficiency and
chronic mucocutaneous candidiasis. Other APS types
are multigenic disorders and occur in adulthood [40].
A strong association with the HLA complex, mainly
DR3-DQ2 and DR4-DQ8, could be an explanation for
the coexistence of CD and other autoimmune disorders
[45–49]. It was stated in a course of self study that the
frequency of CD was significantly higher (p < 0.05) in
the subgroup of patients with Graves’ disease carrying
HLA DRB1*03 alleles [50].
Table VII. Classification of autoimmune polyendocrine syndromes (APS)
Tabela VII. Podział autoimmunologicznych zespołów niedoczynności wielogruczołowej (APS)
Authors APS-1 APS-2 APS-3 APS-4
Neufeld et al.,
1980 [44]
AD, candidiasis#,
hypoparathyroidism‡
(at least two present)
AD (always present)
plus AITD
and/or T1DM
AITD plus another AID
(except from AD and
hypoparathyroidism)
Combination of AID
not mentioned in the
previous groups
Eisenbarth et al.,
2004 [43]
AD, candidiasis#,
hypoparathyroidism‡
(at least two present)
AD, AITD, T1DM
(at least two present)
Lewiński 2005, [44] AD, candidiasis#,
hypoparathyroidism‡
(at least two present)
AD (always present)
plus: AITD†, AITD
and T1DM* T1DM
AITD, ABD, T1DM, vitiligo:
(at least two present)
APS-3A: AITD and T1DM
APS-3B: AITD and ABD
APS-3C: AITD plus other organ-
-specific AID (e.g. coeliac disease)
The table shows classification of APS and components of each type according to above-mentioned authors; #candidiasis — chronic candidiasis of
mucosa and skin; ‡hypoparathyroidism — hypoparathyroiditis of autoimmune origin; †Schmidt syndrome; *Carpenter syndrome; AD — Addison’s
disease; AITD — autoimmune thyroid disease; T1DM — type 1 diabetes; AID — autoimmune disease; ABD — Addison-Biermer disease
Table VI. Prevalence of coeliac disease in patients with other
autoimmune disorders and healthy volunteers (modified
according to [4–27])
Tabela VI. Częstość występowania celiakii u pacjentów
z innymi chorobami autoimmunologicznymi i u zdrowych
ochotników (zmodyfikowano na postawie [4–27])
Study group Prevalence of coeliac
disease (%)
Hashimoto’s thyroiditis 0–9.1
Graves’ disease 0–5.5
Addison’s disease 5.4–12.2
Type 1 diabetes mellitus in children 3.0–8.0
Type 1 diabetes mellitus in adults 2.0–5.0
Autoimmune hepatitis 2.9–6.4
Healthy volunteers 0.2–1.0
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Autoimmune disorders
associated with coeliac disease
Type 1 diabetes
The majority of studies released so far concern the pres-
ence of CD with another autoimmune disorder: T1DM.
Prevalence
Research was first performed by paediatricians over
30 years ago. At that time, only the classical form of
CD was diagnosed. Diagnosis was based on symptoms
such as steatorrhoea, malnutrition, and growth and
development disorders in children. The frequency
of CD in patients with T1DM was established at the
level of 1.0–1.5% [51] which was significantly under-
estimated (as it later turned out after the introduction
of serological assays as a diagnostic tool). In recent
investigations, where specific diagnostic tests are
used, the frequency of histologically confirmed CD in
patients with T1DM is estimated at the level of 2–5%
in adults and 3–9% in children [14–16]. According to
some researchers, the following criteria are connected
to a higher prevalence of CD in patients with T1DM:
young age [53], female gender [52], younger age at
diagnosis of T1DM [53].
Clinical manifestations
Among the clinical symptoms suggesting association
of CD with T1DM, apart from typical symptoms, there
may be episodes of hypoglycaemia caused by malab-
sorption. A gluten-free diet for patients with TD1 and
CD can reduce these episodes in some cases. There-
fore, changing the diet of these patients to one which
is gluten-free usually increases insulin requirements,
thus doses of insulin must be changed. We have to
remember that diarrhoea, a clinical feature of CD,
can also occur in association with bowel neuropathy
as observed in T1DM.
Recommendations for diagnostic evaluation
The Polish Diabetes Association, in its guidelines
from 2011, recommends CD screening in children and
young people with T1DM once a year [54]. The Ameri-
can Diabetes Association (ADA), in its guidelines
from 2011, recommends CD diagnosis when there is
an appearance of clinical symptoms, periodic screen-
ing studies of asymptomatic patients with T1DM
and diagnostic tests in all children with recently di-
agnosed T1DM [55]. However, the guidelines of the
National Institute of Health (NIH) from 2004 [56] and
the American Gastroenterological Association (AGA)
[34, 57] from 2006 recommend a diagnostic approach
to CD in patients with T1DM when the symptoms of
CD are present.
Autoimmune thyroid diseases
Studies of the presence of CD among patients with
autoimmune thyroid diseases (AITD) have concerned
mainly individuals with Hashimoto’s thyroiditis (HT).
Because of the different genetic factors of HT and GD,
these two diseases cannot be analysed as one group [58].
Prevalence
There were two studies performed concerning the fre-
quency of CD in patients with GD [4, 5]. In other investiga-
tions patients with GD have constituted only a small sub-
group of patients with AITD (from 18 to 100 individuals).
In these studies, elevated antibody levels, typical of CD,
were present in approximately 3.7% of patients (ranging
from 0 to 7.2%) and CD was finally diagnosed (histological
evaluation) in approximately 2.5% (ranging from 0% to
5.5%) [4–10, 13]. In self studies performed on 238 patients
with GD, an elevated level of antibodies specific to CD
(IgA TTG or IgA EMA) was confirmed in 5.9% of patients
and a histological diagnosis of CD was diagnosed in 3.4%
of patients [59]. In studies estimating the prevalence of
CD in patients with HT, an elevated level of autoantibod-
ies specific to CD was present in approximately 3.9% of
patients (ranging from 0% to 9.1%) [6, 7, 9–13]. Diagnosis
of CD was established in approximately 3.1% (ranging
from 0% to 9.1%) of patients. In all studies carried out so
far, no predisposition to CD in AIDT patients concerned
with age or gender has been observed. In a study in2010,
the frequency of autoimmune diseases in a group of 2,791
patients with GD and 491 patients with HT was 0.9% and
1.0% respectively [60]. The coexistence of CD and AITD
was assessed only according to a questionnaire, which was
probably the reason for the underestimation.
Clinical manifestations
Many patients with HT and GD suffering from CD have
atypical CD. Some symptoms typical of CD such as diar-
rhoea and weight loss can be incorrectly interpreted as
symptoms of hyperthyroidism in GD, which leads to
delayed diagnosis. One of the symptoms which indicate
the possibility of a coexistence of CD and AITD (HT or
GD after radical treatment) is related to situations con-
nected to hypothyroidism. In these cases, often a higher
dose of levothyroxine (up to 200 ug per day and more)
is required and a gluten-free diet leads, after some time,
to a reduction in doses of hormonal substitution.
Recommendations for diagnostic evaluation
Currently, there are no indications from the Polish En-
docrine Society concerning establishing a diagnosis of
CD in patients with HT and GD. The NIH (2004) [56]
and the AGA (2006) [4, 57] recommend a diagnostic
approach towards CD in patients with AIDT in case of
the appearance of CD symptoms.
247
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SZKOLENIE
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Other autoimmune disorders
Research projects concerning the presence of CD
among other autoimmune disorders are numerous and
are usually performed on small groups of patients. In
a couple of published studies regarding patients with
primary adrenal insufficiency, in various groups of 17
to 109 patients, a diagnosis of CD was established in
5.4% to 12.2% of patients [17, 20]. Authors focus on the
possibility of similar symptoms in both diseases, which
leads to a postponement in establishing a diagnosis
of CD (losing weight, abdominal pain, diarrhoea). In
numerous case reports, there is some data about the
coincidence of CD and primary hypoparathyroidism of
autoimmune origin [61–63]. It is important to remember
this, especially in patients with deep hypocalcaemia ac-
companied by the symptoms of tetany. As opposed to
this situation in which parathormone serum concentra-
tion is low, in patients with hypocalcaemia, connected
to malabsorption in CD, an elevation of serum PTH
concentration may occur.
There is some data regarding CD and its coexist-
ence with lymphocytic hypophysitis [64], alopecia
areata [65–67], and pernicious anaemia. It is essential to
remember that megaloblastic anaemia of B12 vitamin
deficiency can be caused by poor absorption in patients
with CD and the presence of autoantibodies in patients
with pernicious anaemia as well. As a result, when CD is
associated with pernicious anaemia there are indications
for a diagnostic evaluation of the presence of autoim-
mune features (autoantibodies to intrinsic factor).
Studies estimating the prevalence of autoimmune
diseases in patients with CD relate to a much larger
group of patients. Among these studies, the vast major-
ity concern AIDT and Addison’s disease. In a study of
14,021 patients with CD compared to a control group of
68,068, for the first time a significant increase in AITD
was diagnosed (HR = 2.9; 95% Cl = 2.0–4.2; p < 0.001)
[68]. In another study performed by the same authors
on the same group of patients with CD, a higher preva-
lence of Addison’s disease was observed compared to
a healthy control group (HR = 11.4; 95% Cl = 4.4–29.6;
p < 0.001) [69].
Recommendations concerning
the diagnostic approach to coeliac disease
in patients with autoimmune disorders
Recommendations concerning the diagnostic approach
to CD in patients with autoimmune disorders are am-
biguous and differ according to which autoimmune
disease is present, and the Society summarising the data.
At present, the most up-to-date and strict guidelines are
those formulated by the ADA. There are no guidelines
from Polish Societies, apart from the Polish Diabetes
Society. This probably stems from a lack of data con-
cerning the prevalence of CD in the Polish population
of patients with other than T1DM autoimmune disor-
ders. According to the present guidelines of the NIH
(2004) [56] (Tab. VIII) [34, 57], patients with autoimmune
disorders should undergo a diagnostic approach to CD
in the presence of any symptoms suggesting CD. With
relevance to atypical or even silent course of CD types,
it may lead to lower detectability.
It would require further clinical studies on larger
groups of patients with autoimmune disorders to
estimate the prevalence of CD in these patients, and
potential modification of the guidelines.
Remember!
CD is one of the most frequent diseases of autoim-
mune origin, diagnosed, on average, in one out of 100
Table VIII. Recommendations concerning the diagnostic approach to coeliac disease in adult patients based on NIH
recommendations [56]
Tabela VIII. Zalecenia dotyczące diagnostyki celiakii u dorosłych oparte na zaleceniach NIH [56]
Diagnostic approach to coeliac disease Diagnostic approach to coeliac
disease in symptomatic patients
Diagnostic approach to coeliac disease not
recommended
Malabsorption, isolated iron deficiency Family history of coeliac disease General population
Infertility Autoimmune thyroid disease Short history of symptoms from digestive system
Osteoporosis Sjögren’s syndrome Type 1 diabetes**
Ataxia and polyneuropathy Type 1 diabetes*
Arthritis of unknown origin Addison’s disease
Chronic liver disease of unknown origin Symptoms from digestive system
Dermatitis herpetiformis
Irritable bowel syndrome
*With symptoms of coeliac disease, **without symptoms of coeliac disease
248
Coeliac disease and other autoimmune disorders Piotr Miśkiewicz et al.
SZKOLENIE
PODYPLOMOWE
individuals. The results of studies indicate that there is
an increased prevalence of CD in patients with other
diseases of autoimmune origin. The coexistence of CD
with other autoimmune diseases is probably connected
to a common genetic predisposition.
The majority of adult patients suffer from atypical or
silent types of the disease, something which postpones
proper diagnosis. CD, if undiagnosed or untreated, can
lead to many medical disorders.
The diagnostic approach to CD is based on serologi-
cal evaluation (specific antibodies — IgA TTG and IgA
EMA of equivalent diagnostic accuracy). In many cases,
an evaluation of IgA TTG can be routinely considered
as a screening test. A patient with a positive serological
evaluation should undergo endoscopy with a biopsy of
the descending part of the duodenum.
Introducing a strict gluten-free diet in patients with
CD can decrease the risk of many of the medical disor-
ders mentioned above.
In patients with endocrinopathies of autoimmune
origin, in the diagnostic process of many symptoms
and diseases (for example iron deficiency, non-specific
abdominal symptoms, abnormal serum transaminases,
infertility), the coexistence of CD should always be
considered.
References
1. Szajewska H. Digestion and absorbtion disorders. Celiac disease. Szcze-
klik A. Internal Medicine. Practical Medicine. Kraków 2010: 856–861.
2. Gee SJ. On the celiac affection. St Bartholomew’s Hosp Rep. 1888; 24:
17–20.
3. Dicke WK, Weijers HA, van de Kamer JH. Coeliac disease. The presence
in wheat of a factor having a deleterious effect in cases of coeliac disease.
Acta Paediatr 1953; 42: 34–42.
4. Ch’ng CL, Biswas M, Benton A et al. Prospective screening for coeliac
disease in patients with Graves’ hyperthyroidism using anti-gliadin
and tissue transglutaminase antibodies. Clin Endocrinol (Oxf). 2005;
62: 303–306.
5. Mankai A, Chadli- Chaieb M, Saad F, et al. Screening for celiac disease
in Tunisian patients with Graves’ disease using anti-endomysium and
anti-tissue transglutaminase antibodies. Gastroenterol Clin Biol 2006;
30: 961–964.
6. Collin P, Salmi J, Hällström O et al. Autoimmune thyroid disorders and
coeliac disease. Eur J Endocrinol. 1994; 130: 137–140.
7. Sategna-Guidetti C, Bruno M, Mazza E et al. Autoimmune thyroid dise-
ases and coeliac disease. Eur J Gastroenterol Hepatol 1998; 10: 927–931.
8. Berti I, Trevisiol C, Tommasini A et al. Usefulness of screening program
for celiac disease in autoimmune thyroiditis. Dig Dis Sci 2000; 45: 403–406.
9. Va l e n t i n o R , S a v a s t a n o S , Tom m a s e l l i A P e t a l . P r e v a l e n c e o f c o e l i a c d i s e -
ase in patients with thyroid autoimmunity. Horm Res 1999; 51: 124–127.
10. Carroccio A, Custro N, Montalto G et al. Evidence of transient IgA
anti-endomysial antibody positivity in a patient with Graves’ disease.
Digestion 1999; 60: 86–88.
11. Volta U, Ravaglia G, Granito A et al. Coeliac disease in patients with
autoimmune thyroiditis. Digestion 2001; 64: 61–65.
12. Ravaglia G, Forti P, Maioli F et al. Increased prevalence of coeliac disease
in autoimmune thyroiditis is restricted to aged patients. Exp Gerontol
2003; 38: 589.
13. Spadaccino AC, Basso D, Chiarelli S et al. Celiac disease in North Italian pa-
tients with autoimmune thyroid diseases. Autoimmunity 2008; 41: 116–121.
14. Szypowska A, Błazik M, Groele L et al. The prevalence of autoimmune
thyroid disease and celiac disease in children and adolescents with type 1
diabetes mellitus. Endokrynol Diabetol 2008; 14: 221–224.
15. Li Voon Chong JS, Leong KS et al. Is coeliac disease more prevalent in
young adults with coexisting type 1 diabetes mellitus and autoimmune
thyroid disease compared with those with type 1 diabetes mellitus alone?
Diabet Med 2002; 19: 334–337.
16. Sjöberg K, Eriksson KF, Bredberg A et al. Screening for coeliac disease in
adult insulin-dependent diabetes mellitus. Intern Med 1998; 243: 133–140.
17. Biagi F, Campanella J, Soriani A et al. Prevalence of coeliac disease in
Italian patients affected by Addison’s disease. Scand J Gastroenterol
2006; 41: 302–305.
18. Betterle C, Lazzarotto F, Spadaccino AC et al. Celiac disease in North
Italian patients with autoimmune Addison’s disease. Eur J Endocrinol
2006; 154: 275–279.
19. Myhre AG, Aarsetoy H, Undlien DE et al. High frequency of coeliac
disease among patients with autoimmune adrenocortical failure. Scand
J Gastroenterol 2003; 38: 511–515.
20. O’Leary C, Walsh CH, Wieneke P et al. Coeliac disease and autoimmune
Addison’s disease: a clinical pitfall. QJM 2002; 95: 79–82.
21. Fasano A, Berti I, Gerarduzzi T et al. Prevalence of celiac disease in at-risk
and not-at-risk groups in the United States: a large multicenter study.
Arch Intern Med 2003; 163: 286–292.
22. Henker J, Lösel A, Conrad K et al. Prevalence of asymptommatic coeliac
disease in children and adults in the Dresden region of Germany. Dtsch
Med Wochenschr 2002; 127: 1511–1515.
23. Johannsson GF, Kristjansson G, Cariglia N et al. The Prevalence of Celiac
Disease in Blood Donors in Iceland. Dig Dis Sci 2009; 54: 348–350.
24. Roka V, Potamianos SP, Kapsoritakis AN et al. Prevalence of coeliac
disease in the adult population of central Greece. Eur J Gastroenterol
Hepatol 2007; 19: 982–987.
25. Rostami K, Mulder CJ, Wer re JM et al. High prevalence of celiac disease
in apparently healthy blood donors suggests a high prevalence of un-
diagnosed celiac disease in the Dutch population. Scand J Gastroenterol
1999; 34: 276–279.
26. Sanders DS, Patel D, Stephenson TJ et al. A primary care cross-sectional
study of undiagnosed adult coeliac disease. Eur J Gastroenterol Hepatol
2003; 15: 407–413.
27. Volta U, Bellentani S, Bianchi FB et al. High prevalence of celiac disease
in Italian general population. Dig Dis Sci 2001; 46: 1500–1505.
28. Czaja-Bulsa G, Mokrzycka M, Wójcik K et al. Incidence of coeliac
disease in the region of Western Pomerania. Pol. Gastroenterol 1999;
6: 363–369.
29. Czerwionka-Szaflarska M, Swincow G, Szaflarska- Szczepanik A et
al. Incidence of gluten sensitive enteropathy in children of bydgoskie
province in recent twenty years. Prz. Pediatr. 1996; 26: 45–50.
30. Domagała Z. Prevalence of celiac disease in children of kieleckie prov-
ince. Przegl Pediatr 1996; 26: 51–57.
31. Dziechciarz P, Rujner J, Michałowicz-Wojczyńska E et al. Is celiac disease
extinguishing? Epidemiology of celiac disease in Warsaw region in
1975–95. Przegl Pediatr 1996; 26: 58–60.
32. Michałowicz-Wojczyńska E, Konieczny P, Załuska J et al. Incidence of
celiac disease in ostrołęckie and siedleckie province. Przegl Pediatr
1996; 26: 67–74.
33. Romańczuk W, Korczowski R, Kamiński J. Prevalence of celiac disease
in children from south-east part of Poland in 1986–1997. Pediatr Pol
1999; 74: 119–124.
34. AGA Institute. AGA Institute Medical Position Statement on the Diag-
nosis and Management of Celiac Disease. Gastroenterology 2006; 131:
1977–1980.
35. Catassi C, Fabiani E, Rätsch IM et al. The coeliac iceberg in Italy. A multi-
centre antigliadin antibodies screening for coeliac disease in school-age
subjects. Acta Paediatr Suppl. 1996; 412: 29–35.
36. Cilleruelo ML, Román E, Jiménez J et al. Silent celiac disease: explor-
ing the iceberg in the school-aged population. An Esp Pediatr 2002;
57: 321–326.
37. Chorzelski TP, Sulej J, Tchórzewska H et al. IgA class endomysium an-
tibodies in dermatitis herpetiformis and coeliac disease. Ann N Y Acad
Sci 1983; 420: 325–334.
38. Kagnoff MF. Overview and pathogenesis of celiac disease. Gastroenterol-
ogy. 2005 Apr; 128: S10–8.
39. Betterle C, Zanchetta R. Update on autoimmune polyendocrine syn-
dromes (APS). Acta Biomed 2003; 74: 9–33.
40. Lewiński A. Autoimmune polyglandular syndromes. Szczeklik A. Inter-
nal Medicine. Practical Medicine. Kraków 2010: 1235–1242.
41. Bett erle C, Lazzar otto F, Preso tto F. Aut oimmune po lyglan dular
syndrome Type 2: the tip of an iceberg? Clin Exp Immunol 2004;
137: 225–233.
42. Sbarbati A, Valletta E, Bertini M et al. Gluten sensitivity and ‘normal’
histology: is the intestinal mucosa really normal? Dig Liver Dis 2003;
35: 768–773.
43. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes.
N Engl J Med 2004; 350: 2068–2079.
44. Neufeld M, Blizzard RM. Polyglandular autoimmune diseases. In:
Pinchera A, Doniach D, Fenzi GF, Baschieri L. Symposium on Autoim-
mune Aspects of Endocrine Disorders. New York: Academic Press;
1980: 357–365.
45. Kagnoff MF. Overview and pathogenesis of celiac disease. Gastroenterol-
ogy. 2005; 128: S10–18.
249
Endokrynologia Polska/Polish Journal of Endocrinology 2012; 63 (3)
SZKOLENIE
PODYPLOMOWE
46. Bilbao JR, Calvo B, Aransay AM et al. Conserved extended haplotypes
discriminate HLA-DR3-homozygous Basque patients with type 1 diabe-
tes mellitus and celiac disease. Genes Immun. 2006; 7: 550–554.
47. Barker JM, Yu J, Yu L, Wang J et al. Autoantibody “subspecificity” in
type 1 diabetes: risk for organ-specific autoimmunity clusters in distinct
groups. Diabetes Care 2005; 28: 850–855.
48. Barker JM. Clinical review: Type 1 diabetes-associated autoimmunity:
natural history, genetic associations, and screening. J Clin Endocrinol
Metab 2006; 91: 1210–1217.
49. Cuddihy RM, Bahn RS. Lack of an independent association between
the human leukocyte antigen allele DQA1*0501 and Graves’ disease.
J Clin Endocrinol Metab 1996; 81: 847–849.
50. Miśkiewicz P, Bartoszewicz Z, Ambroziak U et al. The prevalence of celiac
disease in patients with Graves’ disease is associated with HLA-DRB1*03
but not with CTLA-4 rs3087243 (CT60) polymorphism. The Endocrine
Society’s Annual Meeting 2009. Washington DC.
51. Thain ME, Hamilton JR, Ehrlich RM. Coexistence of diabetes mellitus
and celiac disease. J Pediatr 1974; 85: 527–529.
52. Mahmud FH, Murray JA, Kudva YC et al. Celiac disease in type 1
diabetes mellitus in a North American community: prevalence,
serologic screening, and clinical features. Mayo Clin Proc 2005;
80: 1429–1434.
53. Hansen D, Bennedbaek FN, Hansen LK et al. High prevalence of coeliac
disease in Danish children with type I diabetes mellitus. Acta Paediatr
2001; 90: 1238–1243.
54. Zalecenia kliniczne dotyczące postępowania u chorych na cukrzycę
2011. Stanowisko Polskiego Towarzystwa Diabetologicznego. Diabetol
Prakt 2011; 12 (Suppl A).
55. Standards of Medical Care in Diabetes 2011. Diabetes Care December
2010 (34): Supplement 1 S4–S10.
56. NIH Consensus Development Conference on Celiac Disease. NIH
Consens State Sci Statements 2004; 28–30.
57. AGA Institute. AGA Institute medical position statement on the
diagnosis and management of celiac disease gastroenterology. 2006;
131: 1977–1980.
58. Zeitin AA, Heward JM, Newby PR et al. Analysis of HLA class II genes in
Hashimoto’s thyroiditis reveals differences compared to Graves’ disease.
Genes Immun 2008; 9: 358–363.
59. Miśkiewicz P, Bartoszewicz Z, Gos-Zajac A et al. Prevalence of Celiac
Disease in Patients with Graves’ Disease. The Endocrine Society Confer-
ence June 15–18. 2008; San Francisco.
60. Boelaert K, Newby PR, Simmonds MJ et al. Prevalence and relative risk
of other autoimmune diseases in subjects with autoimmune thyroid
disease. Am J Med 2010; 123: 183. e1–9.
61. Kumar V, Valeski JE, Wortsman J. Celiac disease and hypoparathyroidism:
cross-reaction of endomysial antibodies with parathyroid tissue. Clin
Diagn Lab Immunol 1996; 3: 143–146.
62. Khandwala HM, Chibbar R, Bedi A. Celiac disease occurring in a patient
with hypoparathyroidism and autoimmune thyroid disease. South Med
J. 2006; 99: 290–292.
63. Matsueda K, Rosenberg IH. Malabsorption with idiopathic hypopar-
athyroidism responding to treatment for coincident celiac sprue. Dig
Dis Sci 1982; 27: 269–273.
64. Collin P, Hakanen M, Salmi J et al. Autoimmune hypopituitarism in
patients with coeliac disease: symptoms confusingly similar. Scand
J Gastroenterol 2001; 36: 558–560.
65. Corazza GR, Andreani ML, Venturo N et al. Celiac disease and alopecia
areata: report of a new association. Gastroenterology 1995; 109: 1333–1337.
66. Bardella MT, Marino R, Barbareschi M et al. Alopecia areata and coeliac
disease: no effect of a gluten-free diet on hair growth. Dermatology
2000; 200: 108–110.
67. Barbato M, Viola F, Grillo R et al. Alopecia and coeliac disease: report of
two patients showing response to gluten-free diet. Clin Exp Dermatol
1998; 23: 236–237.
68. Elfström P, Montgomery SM, Kämpe O et al. Risk of thyroid disease indi-
viduals with celiac disease. J Clin Endocrinol Metab 2008; 93: 3915–3921.
69. Elfström P, Montgomery SM, Kämpe O et al. Risk of primary adrenal
insufficiency in patients with celiac disease. J Clin Endocrinol Metab
2007; 92: 3595–3598.
70. Farr ell RJ , Kelly CP. Celi ac spr ue. N Engl J Med 20 02; 34 6: 18 0–188 (revi ew).
