References:References:1.Professor David S Sanders1.Professor David S Sanders

Consultant GastroenterologistConsultant GastroenterologistRoyal Hallamshire Hospital & University of SheffieldRoyal Hallamshire Hospital & University of Sheffield

2. 2. Alessio Fasano& Carlo Catassi; NEJM 20 Dec 2012.NEJM 20 Dec 2012.3.3.

The Spectrum of Gluten –related disorders!:The Spectrum of Gluten –related disorders!:Celiac-sensitivity-allergy.Celiac-sensitivity-allergy.

What will I learn today? (I hope!)

Is there an evidence base for Gluten

Sensitivity?

The intimate relationship between mankind and wheat

The Prevalence of Adult Coeliac The Prevalence of Adult Coeliac Disease in the UK is 1%!Disease in the UK is 1%!

• CD in Northern Ireland 1 in 122 (n=1823)CD in Northern Ireland 1 in 122 (n=1823)Johnston SD et al Johnston SD et al LancetLancet 1997;350:1370 1997;350:1370

• CD in Sheffield 1 in 100 (n=1200)CD in Sheffield 1 in 100 (n=1200)

Sanders DS et al Sanders DS et al Eur J Gastroenterol HepatolEur J Gastroenterol Hepatol 2003;15:407-13 2003;15:407-13

• CD in Cambridge 1.2% (n=7550)CD in Cambridge 1.2% (n=7550)West J et al West J et al GutGut 2003;52:960-5 2003;52:960-5

• CD in Bristol 1% (n=5470)CD in Bristol 1% (n=5470)Bingley P et al Bingley P et al BMJBMJ 2004;328:322-3 2004;328:322-3

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):1217-25Rubio-Tapia A et al Gastroenterology 2009;137(1):88-93Catassi C et al Ann Med 2010;42(7):530-8

New concepts about coeliac New concepts about coeliac disease!disease!

Fassano A & Catassi C Fassano A & Catassi C Gastroenterology Gastroenterology 2001;120:636-512001;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

Normal & coeliac duodenal mucosa

No crypt hyperplasia

Normal numbers of IEL’s

Increased IEL’s Villous atrophyCrypt hyperplasia

Normal villous architecture

Recognising CD in Recognising CD in GastroenterologyGastroenterology

• Dyspepsia/Reflux Bardella MT et al Arch Intern Med 2000;160:1489-91

• EndoscopyDickey W et al Am J Gastroenterol 1999;94:2182-6

• IBSSanders DS et al Lancet 2001;358:1504-8Sanders DS Gastroenterology 2002;123:1408

• NSAP (non-specific abdominal pain)Sanders DS et al Ann Surg 2005;242:201-7

• Anaemia (Iron, Vitamin B12 and Folate)• Family history (1st degree relative) ~

10% risk

coeliac disease = VA in the

presence of EMA or T

TG

positive!

Pitfalls in SerologyAntibody 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 Hepatol2005;17:85-91.

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

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

Catassi C et al Ann Med 2010;42(7):530-8Wu J et al Gut 2010;59(3):418-9

Biagi F & Corazza GR Biagi F & Corazza GR Nat Rev Gastroenterol Hepatol 2010

Why is the prevalence increasing?

The epidemiological ‘iceberg model’ of coeliac disease

Hopper AD et al BMJ 2007;335:558-62

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

What is potential coeliac disease?

Potential • The presence of EMA (and

perhaps now high levels of TTG?)• High Intraepithelial Lymphocyte

(IEL) counts• In uncomplicated coeliac disease

IEL’s express CD3+ & CD8+ (T suppressor/cytotoxic phenotype) and there is an increase in γδ T-cells

• A positive rectal gluten challenge!

Ferguson A et al Gut 1993;34:150-1

Troncone R et al Acta Paediatr Suppl

1996;412:10-14

Potential coeliac disease =

gluten sensitivity

!

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

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, controlledclinical study. Gastroenterology 2009;136: 816-823

Marsh 1 with +ve EMA

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

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

Neurological manifestations of coeliac disease and gluten sensitivity

Lancet 1998

Dietary treatment of gluten neuropathy

Muscle and Nerve 2006

Does cryptic gluten sensitivity

play a part in neurological illness?

1996 Lancet

Autoantibody target of brain and intestinal transglutaminase

in gluten ataxia

2006Neurology

Gluten sensitivity:from gut to brain

2010Lancet Neurology

Gluten ataxia

2003JNNP

Dietary treatment of gluten ataxia

Isolated gliadin antibodies are prevalent in the general

population but more prevalent in IBS

Sanders DS EJGH 2003 & Lancet 2001

GS

CDIBS

CD+

IBS

GS (extraintestinal)

GS + IBS

?

CD

IBS

GS

Coeliac Disease

Irritable BowelSyndrome

Gluten Sensitive

A Model for the relationship between coeliac disease, IBS and gluten sensitivity?

Ball A and Sanders DS Am J Gastroenterol 2010;105:222-3

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.

Gluten Sensitivity & Irritable Bowel Type Symptoms

• N=102 (35% CD HLA type) • HLA type predicted response to GFDWahanschaffe U et al Gastroenterology 2001;121:1329-38

Wahanschaffe U et al Clin Gastroenterol Hepatol 2007;5:844-50

Non-celiac gluten intolerance may exist

Biesiekierski JR et al Am J Gastroenterol 2011;106:508-14

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

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