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Celiac disease, Diabetes & Crohn disease: An autoimmune implosion ?

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Hakim Rahmoune at University Ferhat Abbas of Setif
Hakim Rahmoune
Nada Boutrid at University Ferhat Abbas of Setif
Nada Boutrid
Mounira Amrane at University Ferhat Abbas of Setif
Mounira Amrane
Ahmed Aziz Bousfiha at University of Hassan II Casablanca
Ahmed Aziz Bousfiha
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Abstract

The autoimmune-related basis in the pathogenesis of celiac disease is merely supported by the increased frequency of association with other autoimmune disorders. We present a peculiar case report associating three different autoimmune disorders in a teenage boy: Celiac Disease , Type1 Diabetes and Crohn Disease
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International Journal of Celiac Disease, 2018, Vol. 6, No. x, xx
Available online at http://pubs.sciepub.com/ijcd/6/2/3
©Science and Education Publishing
DOI:10.12691/ijcd-6-2-3
Celiac Disease, Diabetes & Crohn Disease:
An Autoimmune Implosion?
Hakim Rahmoune1,2,*, Nada Boutrid1,2, Mounira Amrane2,3, Ahmed Aziz Bousfiha4, Belkacem Bioud1,2
1Department of Pediatrics, University Hospital of Setif; Setif 1 University, Algeria
2Genetic, Cardiovascular & Nutritional Diseases Laboratory; Setif-1 University, Algeria
3Central Laboratory, CAC Hospital of Setif; Setif-1 University, Algeria
4Pediatric Clinical Immunology Unit, Casablanca Children Hospital; Hassan II University, Morocco
*Corresponding author: rahmounehakim@gmail.com
Abstract The autoimmune-related basis in the pathogenesis of celiac disease is merely supported by the increased
frequency of association with other autoimmune disorders. We present a peculiar case report associating three
different autoimmune disorders in a teenage boy: Celiac Disease, Type1 Diabetes and Crohn Disease.
Keywords: celiac disease, diabetes mellitus type 1, Crohn disease, autoimmunity
Cite This Article: Hakim Rahmoune, Nada Boutrid, Mounira Amrane, Ahmed Aziz Bousfiha, and Belkacem
Bioud, “Celiac Disease, Diabetes & Crohn Disease: An Autoimmune Implosion?” International Journal of Celiac
Disease, vol. 6, no. x (2018): XX-XX. doi: 10.12691/ijcd-6-2-3.
1. Introduction
Celiac Disease (CD) is an autoimmune disorder triggered by
gluten consumption in genetically susceptible individuals and
characterized by the presence of a specific enteropathy [1].
It exhibits an indreasing worldwide prevalence, specially
in North African Maghreb countries [2,3], and is frequently
reported to be associated with other autoimmune conditions [4].
Here is summarized a rare association combining CD,
Type1 Diabetes (T1D) and Crohn Disease (CrD).
2. Case Presentation
We report the case of a young male teenager aged
thirteen and suffering from type 1 diabetes from several
years and difficultly managed for his chronic, complicated
dysglycemia..
He was diagnosed with T1D at age of 6, but could not
achieve a balanced glycemia despite tight follow up and
increasing insulin doses.
He suffers from refractory, watery, painful diarrhea
since a couple of months is revealing a Celiac disease,
confirmed by both serology and histology.
However, a gluten free diet could not reequilibrate his
bowel and, specially, a capricious melena was noted; as
well as persistant dyspepsia.
In fine, the boy was diagnosed (on endoscopy and
histology) with a Crohn disease ... another autoimmune,
chronic and hard-to-manage, condition.
Human leukocyte antigen (HLA) typing was ordered
and confirmed the presence of both HLA DQ2 (leading to
CD and T1D susceptibility) and HLA DR4 (well
recognized as a severeity biomarker in CrD)
3. Discussion
Autoimmune diseases associated to CD are widely and
increasingly reported [4,5].
However, the peculiar association of these three
conditions (e.g CD, T1D and Crohn Disease) is very
uncommon: we performed a Medline search through
Pubmed® using the Medical Subheading (Mesh) terms:
"Diabetes Mellitus, Type 1", "Celiac Disease" and "Crohn
Disease" with a final search request:
"Diabetes Mellitus, Type 1"[Mesh]) AND "Celiac
Disease"[Mesh]) AND "Crohn Disease"[Mesh] "
Surprisingly, we retrieved only thirteen articles, and no
similar case report using the Pubmed® Search Filter:
‘‘Case Report’’. [6]
Several pathophysiological similarities may explain this
particular association:
-Immunity, at first: the autoimmune-related background
of CD is confirmed by the frequent associations between
different autoimmune disorders and CD. The association
of CD and autoimmune disorders can be explained by the
frequent finding of organ-specific autoantibodies, similar
lymphocyte and mononuclear cell infiltrations at target
organ level, and common HLA phenotypes [7].
- Genetics: mainly through the above mentioned HLA.
Associations between HLA antigens and autoimmune
diseases were reported since the 1970s. After the development
of wide-screen genotyping and finemapping, HLA was
increminated in major autoimmune diseases like CD,
Rheumatoid Arthritis, psoriasis, ankylosing spondylitis,
systemic lupus erythematosus, Type 1 Diabetes, multiple
sclerosis, Graves disease, and dermatomyositis [1,8]
CD is strongly associated with the HLA: more than
95% of patients with CD share the HLA-DQ2 heterodimer,
2 International Journal of Celiac Disease
and the remainder present the HLA-DQ8 heterodimer,
both located on chromosome 6 [9].
In a modern context of increased prevalence of CD as
well as other autoimmune diseases, HLA typing emerges
as an important tool to discriminate individuals genetically
susceptible to develop CD or T1D in at-risk groups such
as those with autoimmune conditions [10].
- Finally, the involvment of intestinal hyperpermeability in
the common genesis of these three conditions [11,12,13],
as well as the expending role of the gastrointestinal
microbiota [14,15,16], complete the puzzle of such an
"autoimmune implosion".
4. Conclusion
Several autoimmune disorders may share, at least
partially, the same immunogenetic core (i.e. HLA) that
could be analysed in the early management of targetted
autoimmune conditions in order to guide future treatment.
Keep in mind that an autoimmune dysregulation may
predispose to other ones with a potential deep impact on
clinical management.
Acknowledgements
The authors would thank the biochemistry laboratory at
University Hospital of Setif for kind collaboration.
References
[1] Rahmoune H, Boutrid N, Bioud B. HLA & Celiac Disease.
Moroccan Health Journal, 2017; 18: 14-15.
[2] Catassi C, Ratsch IM, Gandolfi L, Pratesi R, Fabiani E, El Asmar
R, Frijia M, Bearzi I, Vizzoni L. Why is coeliac disease endemic
in the people of the Sahara?. The Lancet. 1999 Aug 21; 354(9179):
647-8.
[3] Barada K, Bitar A, Mokadem MA, Hashish JG, Green P. Celiac
disease in Middle Eastern and North African countries: a new
burden? World J Gastroenterol 2010; 16: 1449-1457.
[4] Fasano A. Systemic autoimmune disorders in celiac disease.
Current opinion in gastroenterology. 2006 Nov 1; 22(6): 674-9. 7.
[5] Kang JY, Kang AH, Green A, Gwee KA, Ho KY. Systematic
review: worldwide variation in the frequency of coeliac disease
and changes over time. Alimentary pharmacology & therapeutics.
2013 Aug 1; 38(3):226-45.
[6] https://www.ncbi.nlm.nih.gov/pubmed .accessed on april 20th,
2018.
[7] Volta U, De LF, Molinaro N, Tetta C, Bianchi FB. Organ-specific
autoantibodies in coeliac disease: do they represent an
epiphenomenon or the expression of associated autoimmune
disorders?. Italian journal of gastroenterology and hepatology.
1997 Feb; 29(1):18-21.
[8] Pallav K, Kabbani T, Tariq S, Vanga R, Kelly CP, Leffler DA.
Clinical utility of celiac disease-associated HLA testing. Dig Dis
Sci 2014; 59: 2199-206.
[9] https://emedicine.medscape.com/article/1790189. accessed on
april 20th, 2018.
[10] Rahmoune H, Boutrid N, Amrane M, Bioud B. HLA genes as a
predictive screening tool for celiac disease. Turk Pediatri Ars 2017;
52: 182-4.
[11] Fasano A. Leaky gut and autoimmune diseases. Clinical reviews
in allergy & immunology. 2012 Feb 1; 42(1): 71-8.
[12] Krug SM, Schulzke JD, Fromm M. Tight junction, selective
permeability, and related diseases. InSeminars in cell &
developmental biology 2014 Dec 1 (Vol. 36, pp. 166-176).
Academic Press.
[13] Teshima CW, Dieleman LA, Meddings JB. Abnormal intestinal
permeability in Crohn's disease pathogenesis. Annals of the New
York Academy of Sciences. 2012 Jul 1; 1258(1): 159-65.
[14] Cenit MC, Codoñer-Franch P, Sanz Y. Gut microbiota and risk of
developing celiac disease. Journal of clinical gastroenterology.
2016 Nov 1; 50: S148-52.
[15] Chan D, Kumar D, Mendall M. What is known about the
mechanisms of dietary influences in Crohn's disease?. Nutrition.
2015 Oct 1; 31(10): 1195-203.
[16] Needell JC, Zipris D. The role of the intestinal microbiome in type
1 diabetes pathogenesis. Current diabetes reports. 2016 Oct 1;
16(10): 89.
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