GIT J Club Gluten-related diseases.

1. The Spectrum of Gluten –related disorders!:
Celiac-sensitivity-allergy.
References:
1.Professor David S Sanders
Consultant Gastroenterologist
Royal Hallamshire Hospital & University of Sheffield
2. Alessio Fasano& Carlo Catassi; NEJM 20 Dec 2012.
3.

2. What will I learn today?
(I hope!)
Is there an evidence
base for Gluten
Sensitivity?
The intimate relationship
between mankind and
wheat

3. The Prevalence of Adult Coeliac
Disease in the UK is 1%!
• CD in Northern Ireland 1 in 122 (n=1823)
Johnston SD et al Lancet 1997;350:1370
• CD in Sheffield 1 in 100 (n=1200)
Sanders DS et al Eur J Gastroenterol Hepatol 2003;15:407-13
• CD in Cambridge 1.2% (n=7550)
West J et al Gut 2003;52:960-5
• CD in Bristol 1% (n=5470)
Bingley P et al BMJ 2004;328:322-3

4. Why is the prevalence increasing?
• Change in endoscopic techniques
• Antibody screening
• Increased awareness of the spectrum of diversity in
the presentation of Coeliac disease
• An actual increase in disease incidence!?
Lohi S et al Aliment Pharmacol Ther 2007;26(9):1217-25
Rubio-Tapia A et al Gastroenterology 2009;137(1):88-93
Catassi C et al Ann Med 2010;42(7):530-8

5. New concepts about coeliac
disease!
Fassano A & Catassi C Gastroenterology 2001;120:636-51
• The commonest age for
presentation is between the
4th to 6th Decade (An adult > a
pediatric disease)
• For every paediatric case
diagnosed there are 9 adult
cases
• For every adult case
diagnosed there are 7 cases
still not recognised
• People with undiagnosed
adult coeliac disease
generally have a normal BMI
and may even be overweight

8. Normal & coeliac duodenal mucosa
Normal villous
Normal numbers of IEL’s No crypt hyperplasia architecture
Increased IEL’s Crypt hyperplasia Villous atrophy

9. Recognising CD in
Gastroenterology
• Dyspepsia/Reflux
Bardella MT et al Arch Intern Med 2000;160:1489-91
• Endoscopy
Dickey W et al Am J Gastroenterol 1999;94:2182-6e
th
• IBS in
= VA TG
r T
Sanders DS et al Lancet 2001;358:1504-8
e
as A o
Sanders DS Gastroenterology 2002;123:1408
ise EM
• NSAP (non-specific abdominal pain)
cal d Surg 2005;242:201-7
Sanders DS et Ann o f
lia ce
c oe en
es ive!
pr it
• Anaemia (Iron, Vitamin B12 and Folate)
os
• Family history (1st degree relative) ~ 10% risk
p

10. Pitfalls in Serology
Antibody negative coeliac disease
• Prevalence at endoscopy 3.9%,
N=2000 (77/2000)
Antibody negative coeliac disease
accounted for 9.1% (7/77) of
cases within this cohort
Hopper AD et al BMJ 2007;334(7596):729
• The prevalence of seronegative
coeliac disease may range 6.4%
-9.1% of all diagnosed cases
Collin P et al Eur J Gastroenterol Hepatol
2005;17:85-91.

12. The ‘Rise’ of Gluten
‘The main objective of the new Society was to provide ...a common
meeting place for workers in various fields of nutrition.’ The very roots of
the Society were geared towards necessarily increasing the production
of wheat’
Copping AM. History of the Nutrition Society. Proc Nutr Soc 1978;37:105-139 .
‘By the end of the 20th century, global wheat output had expanded by 5-
fold’
International Maize and Wheat Improvement Center. CIMMYT 1998

13. Why is the prevalence increasing?
Lohi S et al Aliment Pharmacol Ther
2007;26(9):1217-25
Rubio-Tapia A et al Gastroenterology
2009;137(1):88-93 Wu J et al Gut 2010;59(3):418-9
Catassi C et al Ann Med 2010;42(7):530-8

14. Why is the prevalence increasing?
Biagi F & Corazza GR Nat Rev Gastroenterol Hepatol 2010

15. The epidemiological ‘iceberg
model’ of coeliac disease
Hopper AD et al BMJ 2007;335:558-62

16. What is latent coeliac disease?
Latent – case reports
• Patients with a normal biopsy while on a regular diet
and subsequently have villous atrophy which
improves on a GFD
• Patients who have villous atrophy but do not adhere
to GFD and after 2 years (or more) a repeat biopsy
reveals normal mucosa
Ferguson A et al Gut 1993;34:150-1
Troncone R et al Acta Paediatr Suppl 1996;412:10-14

17. What is potential coeliac
disease?
Potential
e =
• The presence of EMA (and perhaps
as
now high levels of TTG?)
• High Intraepithelial Lymphocyte (IEL)
d ise
iac !
counts
•
el ty
In uncomplicated coeliac disease
co ivi
IEL’s express CD3+ & CD8+ (T
ial sit
suppressor/cytotoxic phenotype) and
nt en
ote n s
there is an increase in γδ T-cells
•
P te
A positive rectal gluten challenge!
gu
FergusonlA et al Gut 1993;34:150-1
Troncone R et al Acta Paediatr Suppl
1996;412:10-14

18. Okay everything makes sense or
does it?!
• N=1320 children with CD associated HLA
• Serological testing at 1 year intervals for 3 years
• 3.7% were TTG positive BUT ~ 50% spontaneously lost the antibody without
starting a GFD
• Is this a regulatory immune response or immune tolerance?
Simell S et al Am J Gastroenterol 2007;102:1-10

19. What diagnostic criteria should we be using in 2012? =
Should we reclassify mild enteropathy as coeliac
disease ? Marsh 1 with +ve EMA
• Raised IELs with +ve EMA were all HLA +ve in this study
Kaukinen et al. Diagnosing mild enteropathy Coeliac disease: A randomised, controlled
clinical study. Gastroenterology 2009;136: 816-823

20. Marsh 1 with +ve EMA

21. What is the role of immunohistochemical markers –
(small bowel mucosa TG-2 specific IgA deposits) in
patients with normal villous architecture?
Koskinen O et al J Paediatr Gastroenterol Hepatol Nutr 2008;47:436-42

22. What is the role of small bowel mucosa TG-2 specific IgA deposits
in patients with normal villous architecture?
• TG-2 targeted intestinal autoantibody deposits – they are
produced in the small bowel mucosa and can deposit on extra-
cellular TG-2 in the intestinal mucosa
Korponay-Szabo IR et al Gut 2004;53:641-8
• TG-2 deposits may allow us to differentiate which patients with
raised gamma/delta IEL’s may be sensitive to gluten
Kaukinen K et al Scand J Gastroenterol 2005;40:5640-72
• Have been valuable in antibody negative coeliac disease
Kaukinen K et al Gut 2006;55:1746-53
In diagnosing mild enteropathy coeliac disease the sensitivity and
specificity was 93%!
Salmi TT et al Aliment Pharmacol Therap 2006;24:541-62

23. Neurological manifestations of coeliac
disease and gluten sensitivity
Dietary treatment of
Gluten ataxia gluten neuropathy
Lancet
Muscle and Nerve
1998 Dietary treatment 2006
of gluten ataxia
1996 2003 2006 2010
Lancet JNNP Neurology Lancet Neurology
Does cryptic gluten Autoantibody target of Gluten sensitivity:
sensitivity brain and intestinal from gut to brain
play a part in transglutaminase
neurological illness? in gluten ataxia

24. Isolated gliadin antibodies are prevalent in the general population
but more prevalent in IBS
Sanders DS EJGH 2003 & Lancet 2001

25. CD CD
+
IBS IBS
?
GS
+ IBS
CD Coeliac Disease
GS IBS Irritable Bowel
Syndrome
GS Gluten Sensitive
GS (extraintestinal)
A Model for the relationship between coeliac disease, IBS and gluten
sensitivity?
Ball A and Sanders DS Am J Gastroenterol 2010;105:222-3

26. What do IEL’s have to do with IBS?
Causes of Raised Duodenal IELs Number
No cause found but majority with IBS symptoms 34
NSAIDs 21
Coeliac disease 16
Helicobacter pylori 14
Gastrointestinal infection 5
Immune dysregulation 5
Inflammatory bowel disease 4
IgA Deficiency 1
Total 100
Aziz I et al Aliment Pharmacol Therap 2010;32(11-12):1392-7.

27. Gluten Sensitivity & Irritable Bowel
Type Symptoms
• N=102 (35% CD HLA type)
• HLA type predicted response to GFD
Wahanschaffe U et al Gastroenterology 2001;121:1329-38
Wahanschaffe U et al Clin Gastroenterol Hepatol 2007;5:844-50

29. Non-celiac gluten intolerance may exist
Biesiekierski JR et al Am J Gastroenterol 2011;106:508-14

30. This research field is taking off!
Sapone A et al In press BMC 2012

31. The U.S. market for gluten-free food and
beverage products grew at a compound annual
growth rate of 28 percent from 2004 to 2008, to
finish with almost $1.6 billion in retail sales
• Gluten Free
diet
• Low Carb
diet
• Low Fat
diet
The UK retail market is worth £125 million*- when you consider the
healthcare market is only worth around £37 million** and that there
are only around 120,000 diagnosed coeliac patients in the UK then
this may suggest other individuals opting for a gluten-free diet
* Kantar Worldpanel, April 2011
**IMS data