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Coeliac disease and autoimmune Addison’s disease:
a clinical pitfall
C. O’LEARY, C.H. WALSH, P. WIENEKE, P. O’REGAN, B. BUCKLEY,
D.J. O’HALLORAN, J.B. FERRISS, E.M.M. QUIGLEY, P. ANNIS,
F. SHANAHAN and C.C. CRONIN
From the Department of Medicine, National University of Ireland, Cork, Ireland,
and affiliated teaching hospitals
Received 28 November 2000 and in revised form 12 November 2001
Summary
Background: Coeliac disease has an increased pre-
valence in a number of autoimmune endocrine
conditions. An association between coeliac disease
and Addison’s disease has been proposed in isolated
case reports, but has not been formally studied.
Aim: To investigate the extent of this associ ation.
Design: Prospective screening of patients with con-
firmed Addison’s disease.
Methods: From central computerized records, we
identified all living patients with a diagnosis of auto-
immune Addison’s disease in the past 30 years and
presently attending our affiliated hospitals. After
exclusions, 44 were invited to attend for screening.
Results: Of 41 patients screened, five (12. 2%)had
coeliac disease: Three were previously diagnosed
coeliacs and this was confirmed on review, includ-
ing examination of biopsy material. A further two
had positive IgA-endomysial antibodies . Histo-
logical confirmation was obtained in both cases.
Neither had laboratory or clinical evidence of
malabsorption.
Discussion: In this series of patients with Addison’s
disease, a higher co-morbidity with coeliac disease
was observed than in any previously studied endo-
crine condition. We recommend that coeliac sero-
logy (anti-endomysial and tissue transglutaminase
antibody) testing be incorporated routinely into the
autoimmune screen for other conditions in pa tients
with Addison’s disease.
Introduction
The prevalence of coeliac disease in the West of
Europe approaches 0.8%.
1,2
The availability of
specific and sensitive serological tests, particularly
the an ti-endomysial and tissue transglutaminase
antibodies, has facilitated widespread scree ning.
3,4
While the value of serological screening in the
general population is not established, targeted
screening of high-risk population subsets is of parti-
cular clinica l importance. Individuals at risk include
those with a positive family history, and those with
associated autoimmune endocrinopathies.
The increased prevalence of coeliac disease in
the context of autoimmune thyroid disease (5.4%)
and insulin-dependent diabetes mellitus (5.0%)
has received much attention.
5–9
While the impact
of coeliac disease on the clinical course of coexist-
ing autoimmune conditions is unclear, a cause-and-
effect relationship has recently been proposed.
10
Specifically, the duration of gluten exposure has
been repo rted to be linked to the prevalence of
autoimmune disorders in coeliac patients. In those
coeliacs diagnosed after the age of 10 years, the
prevalence of autoimmune disorders is up to
seven-fold higher than in healthy controls.
10
This
further strengthens the argument for early diagnosis
and treatment through appropriate screening.
ß Association of Physicians 2002
Address correspondence to Professor F. Shanahan, Professor of Medicine/Consultant Gastroenterologist, Department
of Medicine, Cork University Hospital, Cork, Ireland. e-mail: FShanahan@ucc.ie
Q J Med 2002; 95:79–82
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Addison’s disease is an endocrine condition in
which co-existing coeliac disease could have
serious clinica l implications. Firstly, there is a
crossover of symptoms between malabsorption
and the vague gastrointestinal symptoms due to
adrenocortical insufficiency, which may compound
clinical diagnosis. Secondly, chronic steroid admin-
istration, albeit at physiological doses, may result in
delayed or atypical presentation of coeliac disease.
Thirdly, malabsorption associated with coeliac
disease may alter steroid bioavailability in patients
with Addison’s disease on replacement doses of
steroids.
Scattered case reports of an associat ion between
coeliac disease and Addison’s disease can be found
in the literature,
11–15
but there has been no formal
study to date. Our objective was to review a series
of patients with autoimmune Addison’s disease and
to estimate the prevalence of coeliac disease in
autoimmune Addison’s disease.
Methods
From central computerized records, we identified
and reviewed all patients with a diagnosis of adrenal
insufficiency in the past 30 years (n = 91). The
diagnosis of primary adrenal insufficiency was con-
firmed on the basis of recognized clinical mani-
festations (Table 1) accompanied by an elevated
ACTH and/or a flat response to dynami c ACTH
testing. Autoimmune adrenalitis was inferred by
the demonstration of positive adrenal antibodies
and/or the exclusion of other aetiologies, particu-
larly infection (including tuberculosis), haemorrhage
and primary or metastatic malignancy.
16,17
Of the 91 patients identified, the following
exclusions were made (Table 2); 13 whose adrenal
insufficiency was secondary to a pituitary tum our or
surgery, four who had tuberculous adrenalitis, three
who had iatrogenic disease, and another who had
Sheehan’s syndrome. Seven patients had died, and
a further 19 patients were excluded either because
they had relocate d outside this catchment area (2),
or because there was insufficient information
available to confirm the diagnosis of autoimmune
Addison’s disease according to the above clinical or
laboratory criteria (17). The remaining 44 patients,
with confirmed autoimmune Addison’s disease
comprised the study population.
IgA anti-endomysial an d/or tissue transglutamin-
ase antibody testing was used to screen for coe liac
disease. All patients with positive serolo gy were
invited to attend for endoscopic distal duodenal
biopsy. Biopsy specimens in those patients with a
previous diagnosis of coeliac disease were reviewed
to confirm the diagnosis. Informed consent was
obtained from all participants. Approval of the study
protocol was obtained from the Clinical Research
Ethics Committee of the Cork Teaching Hospitals.
Results
Of the patients with autoimmune Addison’s disease,
41/44 attended for screening. (21 male, 20 female).
Mean age at diagnosis was 34 years, (range 7–66
years, median 37 years). Mean duration of Addison’s
disease was 10 years, (range 1–30 years, median
9 years). Adrenal antibodies were available and
positive in 29/44 subjects. In the remaining 16
patients, an autoimmune aetiology was inferred by
the exclusion of other causative factors.
Table 3 summarizes the results. Five patients
(5/41, 12.2%) had a new or confirmed diagnosis
of coeliac disease (95%CI 3–21%). Three of these
(A, B, C) were kno wn coeliacs prior to the study.
A further two patients (D, E) were found to have
positive endomysial antibodies on screening, and
endoscopic small-bowel biopsy subsequently con-
firmed coeliac disease. One of these patients had
Table 1 Clinical manifestations of adrenal insufficiency
Primary and secondary adrenal insufficiency
Tiredness, weakness, mental depression
Anorexia, weight loss
Dizziness, orthostatic hypotension
Nausea, vomiting, diarrhoea
Hyponatraemia, hypoglycaemia, mild normocytic
anaemia, lymphocytosis, eosinophilia
Primary adrenal insufficiency and associated disorders
Hyperpigmentation
Hyperkalaemia
Vitiligo
Autoimmune thyroid disease
Central nervous system symptoms in adrenal
myeloneuropathy
From reference 17.
Table 2 Causes of adrenal insufficiency
Aetiology No. of patients
Autoimmune 44
Unknown 19
Pituitary tumour/surgery 13
Deceased 7
Tuberculosis 4
Iatrogenic 3
Infarction 1
C. O’Leary et al.80
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a mild increase in intraepithelial lymphocytes and
blunting of villi, the other had severe partial villous
atrophy. In no patient were the diagnoses made
simultaneously; the interval between diagnoses was
1–30 years.
One of the patients (D) with previously unrecog-
nized coeliac disease reported non-specific
abdominal pain and nausea; the other (E) was
asymptomatic at the time of screening, and on
review of her medical records, there had been no
gastrointestinal symptoms predating the diagnosis
of Addison’s disease. There were no haematological
or biochemical abnormalities. Steroid replacement
doses were within the standard range in both
patients.
Discussion
This is the largest reported series of patients with
coeliac disease and autoimmune Addison’s disease
to date. No cases of Addison’s disease are likely
to ha ve been missed for the period of assessment,
as all such patients are followed at hospital-based
endocrine clinics within the region. The strength of
association between these two conditions (12.2%
in this series) is higher than any other previously
reported endocrine condition. Although a control
group was not studied, the background prevalence
of coeliac disease in the Irish population is -1%.
1
A similar immuno genetic background is one
explanation for the link between these conditions.
The HLA association of coeliac disease is well
characterized. Approximately 95% of patients
possess the (HLA)-DQ (A1*0501, B1*0201) hetero-
dimer, compared to 20–30% of controls.
18
The
inherited susceptibility to autoimmune Addison’s
disease is strongly associated with (HLA)-DR3 and
DR4 alleles.
19
The genotype HLA DQA1*0501 is
significantly more common in Addison’s disease
(70%) than in controls (43%).
20
It is likely that one or more genes at an HLA-
unlinked locus are a stronger determinant of
susceptibility to coeliac disease than HLA.
18
The
CTLA-4 molecule has been assessed as a potential
candidate for this role . The CTLA4 gene exon 1
polymorphism (49 A/G) has recently been demon-
strated to predispose to coeliac disease.
21
In patients
with Addison’s disease, those carrying the suscept-
ibility marker, HLA DQA1*0501, have also been
shown to be significantly more likely to have
this polym orphism than controls with the same
DQA1 allele.
22
The recent demonstration of a relation between
the duration of exposure to gluten and the pre-
valence of autoimmune disorders in coeliac disease
is also of significance in this study.
10
The mean age
at diagnosis of coeliac disease in this group was
57 years with a range of 21–48 years. Two of the
five patients had a second autoimmune disorder
(Table 3).
Autoimmune Addison’s disease is relatively rare ,
with an estimated prevalence of approximately
39 to 60 per million.
17
Its association with coeliac
disease is potentially clinically important, having
both diagnostic and therapeutic imp lications. From
a clinical standpoint, chronic adrenal insufficiency
is often difficult to diagnose. Its onset is insidious
and symptoms can be vague. Typical co mplaints
include chronic malaise, fatigue and generalized
weakness. Gastrointestinal manifestations are pre-
sent in more than 50% of these patients, and
include lower abdominal cramps, anorexia, weight
loss and nausea.
23
Other features common to
coeliac disease include pigmentation, reduced
bone mineral den sity, amenorrhoea, anaemia and
an association with other endo crine conditions.
There have been reports in the literature of
an unmasking of coeliac disease in patients dis-
continuing chronic steroid therapy
24,25
and steroids
have a well-recognized therapeutic role in the
management of refractory coeliac disease. In a
treated Addison’s patient, physiological doses of
steroids, through partial treatment of the mucosal
lesion, may mitigate symptoms and partially
suppress the immune response.
Table 3 Age and mode of presentation of patients with coeliac disease and autoimmune Addison’s disease
Patient Sex Addison’s disease Coeliac disease Other conditions
Age at
diagnosis
Presentation Age at
diagnosis
Presentation
A F 55 Adrenal crisis 30 Dermatitis Hypothyroidism
B F 56 Weight loss, fatigue 43 Fe/folate/B12 deficiency Osteoporosis
C M 22 Screening 21 Diarrhoea IDDM
D F 14 Pigmentation 44 Screening None
E F 32 Fatigue, pigmentation 48 Screening Osteopenia
Ages are in years. IDDM, Insulin-dependant diabetes mellitus.
Addison’s disease and coeliac disease 81
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As a corollary, institution of a gluten-free diet
and subsequent reversal of mucosal abnormal-
ities has implications for optimal treatment of
Addison’s disease. In patients with unrecognized
and untreated coeliac disease, the pharmaco-
kinetics of steroids may be altered; in particular,
those with hypoalbum inaemia may have an
increased volume of distribution and reduced
protein binding.
26
Correction of hypoalbuminaemia
may therefore necessitate a reduction in the
maintenance dose of steroids.
In conclusion, of the previously reported auto-
immune endocrinopa thies, Addison’s disease has
the strongest association with coeliac disease. This
is likely to be related to their similar genetic back-
grounds, alth ough a cause-and-effect relationship
between gluten exposure and autoimmunity has
been raised. We recommend that coeliac serology
be incorporated into the routine screen for auto-
immune conditions in patients with autoimmune
Addison’s disease.
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