Why Are Celiac Disease and Gluten Sensitivity on a Rise?

Why Are Celiac Disease and Gluten Sensitivity on a Rise?

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Description: All disease begins in the gut - Hippocrates 460 BC. The gut is not like Las Vegas: what happens in the gut does not stay in the gut A.F. 2010 AC.

The intestinal mucosa is the battlefield on which friends and foes need to be recognized and properly managed to find the ideal balance between tolerance and immune response. Celiac disease as the ideal paradigm to study how friends can become foes. Celiac Disease as a Unique Model of Autoimmunity: The only autoimmune disease in which specific MHC class II HLA (DQ2 and/or DQ8) are present in >95% of patients; The auto-antigen (tissue Transglutaminase) is known; The environmental trigger (gluten) is known; Elimination of the environmental trigger leads to a complete resolution of the autoimmune process that can be re-ignited following re-exposure to gluten.

 
Author: Alessio Fasano M.D. (Senior) | Visits: 576 | Page Views: 958
Domain:  Medicine Category: Therapy 
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Contents:
Why Are Celiac Disease and
Gluten Sensitivity on a Rise?

Alessio Fasano, M.D.
Mucosal Immunology and Biology Research Center
And Center for Celiac Research
Massachusetts General Hospital, Boston MA – U.S.A.

Lecture Objectives
Gluten + Genes = Celiac Disease
Not So Fast!
Microbiome

Environmental
Factors

Clinic Outcome

All disease begins in the gut Hippocrates 460 BC
The gut is not like Las Vegas: what
happens in the gut does not stay in
the gut –
A.F. 2010 AC
The intestinal mucosa is the battlefield
on which friends and foes need to be
recognized and properly managed to
find the ideal balance between
tolerance and immune response.

Celiac disease as the ideal paradigm to
study how friends can become foes.

The Banana Babies

WK Dicke, 1905 - 1962

1st case of CD at UMB: 1938

Celiac Disease as a Unique
Model of Autoimmunity
•  The only autoimmune disease in which specific
MHC class II HLA (DQ2 and/or DQ8) are present in
>95% of patients;
•  The auto-antigen (tissue Transglutaminase) is
known;
•  The environmental trigger (gluten) is known;
•  Elimination of the environmental trigger leads to
a complete resolution of the autoimmune process
that can be re-ignited following re-exposure to
gluten

Gastrointestinal Manifestations
(“Classic”)
Most common age of
presentation: 6-24 months
• 
• 
• 
• 
• 
• 
• 
• 

Chronic or recurrent diarrhea
Abdominal distension
Anorexia
Failure to thrive or weight loss
Abdominal pain
Vomiting
Constipation
Irritability

Rarely: Celiac crisis

Non Gastrointestinal
Manifestations
Most common age of presentation: older child to adult
•  Dermatitis Herpetiformis
•  Dental enamel hypoplasia
of permanent teeth
•  Osteopenia/Osteoporosis
•  Short Stature
•  Delayed Puberty

•  Iron-deficient anemia
resistant to oral Fe
•  Hepatitis
•  Arthritis
•  Epilepsy with occipital
calcifications

Listed in descending order of strength of evidence

The Clinical Manifestations of Celiac Disease
are More Heterogeneous Than
Previously Appreciated

A. Fasano, N Engl J Med 2003;348:2568-70.

What is the Recipe to
Develop Celiac Disease

The Holy Trinity of the
Autoimmune Mechanisms
in Celiac Disease

Fasano A; Scientific American Aug. 2009

Understanding Why
Gluten is Toxic

THE GRAINS IN THE PAST WERE DIFFERENT
FROM THE CURRENT GRAINS

+

T. turgidum AABB
28 chromosomes
100,000 genes

Aegilops tauschii DD
14 chromosomes
50,000 genes

T. aestivum AABBDD
42 chromosomes
150,000 genes

Pieter Bruegel, 1565

What Is So Special About Gluten?

Gliadin

Glutenin

Gluten (gliadin+glutenin)

Mapping of α-gliadin motifs exerting cytotoxic activity (red), immunomodulatory
activity (light green), zonulin release and gut permeating activity (blue) and CXCR3dependent IL8 release in CD patients (dark green).
Shan L et al, Science. 2002;
297:2275-9.

Lammer K et al, Immunology.
2011;132:432-40

Maiuri et al. Scand J
Gastroenterol. 1996; 31:247-53.

Lammer K et al, Gastroenterology
2008;135:194-204.

Gluten Triggers Biological Responses In Everybody
But Not Everybody Gets Sick Eating Gluten
A.  Epithelial Events
Timeline: Hours (Everybody)

B. Innate Immunity Events
Timeline: Days (GS)

C. Adaptive Immunity Events
Timeline: Weeks-Years (CD)

Clemente MG et al Gut 2003; Drago et al Scand J Gastroenterol 2006; Sapone A. et al. JADD 2010

We Are Not Born With The Destiny
To Develop Celiac Disease

Autoimmunity Epidemics

Celiac Disease Epidemiological
Study in USA
Population screened
13145
Healthy Individuals
4126

Risk Groups
9019
Symptomatic subjects
3236

Positive
31

Negative
4095

Prevalence
1:133

Positive
81

Negative
3155

Prevalence
1:40

1st degree relatives
4508
Positive
205

Negative
4303

Prevalence
1:22

2nd degree relatives
1275
Positive
33

Negative
1242

Prevalence
1:39

Projected number (conservative) of celiac disease patients in the U.S.A.: 2,115,954
MAJOR PUBLIC HEALTH PROBLEM NATIONAWIDE WITH SOME REGIONAL DIFFERENCES
A. Fasano et al., Arch Int Med 2003;163:286-292.

Increased Prevalence Over Time in U.S.A.
(in Line with Other Autoimmune Diseases)
CD prevalence (%)

1.5

0.93%

1.0
0.45%

0.5

0.0
1960

0.21%

1970

1980

1990

2000

2010

year
During the past 35 years the true prevalence of CD in USA
doubled every 15 years.
C. Catassi et al, Annal Med 2010

Celiac Disease
Autoimmune Pathogenesis

+

=

Necessary but NOT Sufficient

Key Questions in
CD Pathogenesis
1.  What kind of tricks were used by people
genetically at risk for CD that were able to
tolerate gluten for decades?
2.  What happened to them that caused the shift
from tolerance to immune response to gluten?

How to Re-Write the
Natural History of CD?

The Epidemics Of Celiac Disease:
Which Additional Factors are
Driving this Epidemics?
- Quality of gluten;
- Quantity of gluten;
- Breast Feeding;
- Timing of gluten introduction
- Maturity of gut functions influencing Ag trafficking and
handling:
- GALT
- PRRs
- Mucous production
- Barrier function

- Changes in microbiome composition.

Published on October 2, 2014

Home Take Messages
•  Window of tolerance concept (4-7 months best period to introduce
baby food) not supported anymore;
•  Breast feeding in general or introduction of gluten while breast feeding
showed no protective effect on CD onset in at-risk infants;
•  Early introduction (16 weeks) of gluten traces to potentially induce
tolerance did not protect against CD in at-risk infants;
•  Delaying the introduction of gluten in at-risk infants does not prevent
CD but merely postpones its onset by approximately 8 months
(significant difference at 2 years FU that disappeared by 5 years FU);
•  GI infections during the first year of life seems not influential in
increased the risk of CD onset;
•  High-risk HLA profiles seems to be the most influential factor predictor
of increased risk of CD onset;
•  The high prevalence of CD among the study cohort suggests that the
CD epidemics continues.

The Epidemics Of Celiac Disease:
Which Additional Factors are
Driving this Epidemics?
- Quality of gluten;
- Quantity of gluten;
- Breast Feeding;
- Timing of gluten introduction
- Maturity of gut functions influencing Ag trafficking and
handling:
- GALT
- PRRs
- Mucous production
- Barrier function

- Changes in microbiome composition.

Which Factors are Driving This
Autoimmunity Epidemics?
Nutrition
Microbiome
Composition
Maturation
GALT

+

Genetic
Predisposition

Immune-Mediated
Diseases

The Complexity of the Human Body
Over the years we
came to appreciate
the complexity of the
human body
Only 25,000 genes, 99.5% identical
to chimpanzee, cannot explain
such complexity and difference
with other primates.

However, it would be inappropriate
to describe the human body without
considering the 300,000,000,000
bacteria (collectively defined as
microbiome) gladly living inside us
and that express ~100 fold more
genes that the human genome.

The Real Story of Our Genetic Complexity:
We Inherit two Parallel Genomes
Human Genome:
Inherited from both parents, stable,
never change in its composition

Microbiome:
Inherited from the mother, extremely
dynamic, changes from individual to
individual and in the same
individual over time

Higher Risk of Celiac Disease After
Elective Cesarean Delivery

Mårild et al Gastroenterology 2012;142(1):39

Human Genome

Microbiome
(140-fold Human Genome)

Dynamic

Metabonome

(~30,000 genes)

Stable
Jazz

Pop

Clinical
Outcome

Classic

Not Only Celiac Disease

Gluten Free Market

For the American general population adopting a gluten-free diet is becoming an
increasingly popular solution. The market for gluten-free food and beverage products
grew at a compound annual growth rate of 28 percent/year from 2004 to 2011, to finish
with almost $6.7 billion in retail sales last year. By 2014 the market is expected to reach
about $10.2 billion in sales.
The fact that approximately 3 million Americans suffer from celiac disease and only a
fraction of these patients have been diagnosed implies that patients suffering of other
forms of proven gluten reaction, including gluten sensitivity and wheat allergy,
contribute to this market growth. The rest of the market is filled by people affected by
maladies claimed to be affected by gluten exposure, including autism, ADHD, multiple
sclerosis, IBS, and ADHD.

The Fad Factor of the GFD

Estimated US GF Retail Market:
• Mintel: $10.5 B in 2013, predicted to raise 48%
to $15.6 B in 2016;
• Packages Facts: $4.2 B in 2012, predicted to
raise 55% to 6.6 B;
• Food Standard Agency: $2.6B in 2011;
• Euromonitor: $486.5 M in 2013 (limited to
products specifically formulated GF)

Change of US GF Market 2011-13:

How Many People in the US Are
Embracing a GFD?:
Percentage of U.S. Adults Trying to Cut
Down or Avoid Gluten in Their Diets
Reaches New High in 2013, Reports
NPD

Why People in the US Embrace a GFD?:
Approx 7M
Approx 9M

Approx 24M

Approx 300,000

Approx 50M

Based on internet interview users age 18y+ who eats GF food

Estimated Prevalence of NCGS:

Low
(0-10%)

Medium
(11-30%)

High
(31-100%)

The Gluten Free Diet:
Not Only Celiac Disease
GLUTEN FREE DIET CONSUMERS

MEDICAL NECESSITY

WHEAT ALLERGY
(IGE-MEDIATED)
(~0.1%)

CELIAC DISEASE
(AUTOIMMUNEBASED)
(~1%)

NO MEDICAL
NECESSITY

GLUTEN SENSITIVITY
(INNATE IMMUNITY?)
(~6%)

Gluten Sensitivity (NCGS): Facts
Definition

Cases of reaction to ingestion of gluten-containing grains in
which both allergic and autoimmune mechanisms have
been ruled out (diagnosis by exclusion criteria)
•  Triggered by the ingestion of gluten-containing grains;
•  Negative immuno-allergy tests to wheat;
•  Negative CD serology (EMA and/or tTG) and in which IgA deficiency
has been ruled out;
•  Negative duodenal histopathology;
•  Possible presence of biomarkers of gluten immune-reaction (AGA+);
•  Presence of clinical symptoms that can overlap with CD or wheat
allergy symptomatology;
•  Resolution of the symptoms following implementation of a GFD and
relapse after re-exposure to gluten-containing grains (double blind)
Sapone A. et al BMC Med 2012, Ludvigsson JF et al Gut 2013, Catassi C. Et al, Nutrients 2013

Non Celiac Gluten Sensitivity:
What is the Magnitude of the Problem?
The CFCR Experience (2004-2010)
• 
• 
• 
• 

Nr. of the patients seen at the CFCR clinic: 5,896
Nr. of patients fulfilling criteria for GS: 347
Prevalence in our cohort: 1:17 (6%)
Symptoms:
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 

Abdominal pain: 68%
Eczema and/or rash: 40%
Headache: 35%
“Foggy mind”: 34%
Fatigue: 33%
Diarrhea: 33%
Depression: 22%
Anemia: 20%
Numbness legs/arms/fingers: 20%
Joint pain: 11%

Gluten Sensitivity and IBS

Am J Gastroenterol. 2011 Mar;106(3):508-14; quiz 515. doi: 10.1038/ajg.2010.487. Epub 2011
Jan 11.
Gluten causes gastrointestinal symptoms in subjects without celiac disease: a doubleblind randomized placebo-controlled trial.
Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, Shepherd SJ,
Muir JG, Gibson PR.
Source
Monash University Department of Medicine and Gastroenterology, Box Hill Hospital, Box Hill, Victoria, Australia.

Abstract
OBJECTIVES:
Despite increased prescription of a gluten-free diet for gastrointestinal symptoms in individuals who do not have celiac disease,
there is minimal evidence that suggests that gluten is a trigger. The aims of this study were to determine whether gluten
ingestion can induce symptoms in non-celiac individuals and to examine the mechanism.
METHODS:
A double-blind, randomized, placebo-controlled rechallenge trial was undertaken in patients with irritable bowel syndrome in
whom celiac disease was excluded and who were symptomatically controlled on a gluten-free diet. Participants received either
gluten or placebo in the form of two bread slices plus one muffin per day with a gluten-free diet for up to 6 weeks. Symptoms
were evaluated using a visual analog scale and markers of intestinal inflammation, injury, and immune activation were
monitored.
RESULTS:
A total of 34 patients (aged 29-59 years, 4 men) completed the study as per protocol. Overall, 56% had human leukocyte
antigen (HLA)-DQ2 and/or HLA-DQ8. Adherence to diet and supplements was very high. Of 19 patients (68%) in the gluten
group, 13 reported that symptoms were not adequately controlled compared with 6 of 15 (40%) on placebo (P=0.0001;
generalized estimating equation). On a visual analog scale, patients were significantly worse with gluten within 1 week for overall
symptoms (P=0.047), pain (P=0.016), bloating (P=0.031), satisfaction with stool consistency (P=0.024), and tiredness
(P=0.001). Anti-gliadin antibodies were not induced. There were no significant changes in fecal lactoferrin, levels of celiac
antibodies, highly sensitive C-reactive protein, or intestinal permeability. There were no differences in any end point in individuals
with or without DQ2/DQ8.
CONCLUSIONS:
"Non-celiac gluten intolerance" may exist, but no clues to the mechanism were elucidated.

No effects of gluten in patients with self-reported non-celiac gluten sensitivity after
dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates.
Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR.
Source
Department of Gastroenterology, Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia; Department
of Gastroenterology, Central Clinical School, Monash University, The Alfred Hospital, Melbourne, Victoria, Australia.

Abstract
BACKGROUND & AIMS:
Patients with non-celiac gluten sensitivity (NCGS) do not have celiac disease but their symptoms improve when they are
placed on gluten-free diets. We investigated the specific effects of gluten after dietary reduction of fermentable, poorly
absorbed, short-chain carbohydrates (fermentable, oligo-, di-, monosaccharides, and polyols [FODMAPs]) in subjects believed
to have NCGS.
METHODS:
We performed a double-blind cross-over trial of 37 subjects (aged 24-61 y, 6 men) with NCGS and irritable bowel syndrome
(based on Rome III criteria), but not celiac disease. Participants were randomly assigned to groups given a 2-week diet of
reduced FODMAPs, and were then placed on high-gluten (16 g gluten/d), low-gluten (2 g gluten/d and 14 g whey protein/d), or
control (16 g whey protein/d) diets for 1 week, followed by a washout period of at least 2 weeks. We assessed serum and
fecal markers of intestinal inflammation/injury and immune activation, and indices of fatigue. Twenty-two participants then
crossed over to groups given gluten (16 g/d), whey (16 g/d), or control (no additional protein) diets for 3 days. Symptoms were
evaluated by visual analogue scales.
RESULTS:
In all participants, gastrointestinal symptoms consistently and significantly improved during reduced FODMAP intake, but
significantly worsened to a similar degree when their diets included gluten or whey protein. Gluten-specific effects were
observed in only 8% of participants. There were no diet-specific changes in any biomarker. During the 3-day rechallenge,
participants' symptoms increased by similar levels among groups. Gluten-specific gastrointestinal effects were not
reproduced. An order effect was observed.
CONCLUSIONS:
In a placebo-controlled, cross-over rechallenge study, we found no evidence of specific or dose-dependent effects of gluten in
patients with NCGS placed diets low in FODMAPs. www.anzctr.org.au. ACTRN12610000524099.

Non Celiac Gluten Sensitivity: Facts
Definition of Food Reactions
(Consensus NIAID 2011)

Food intolerance occurs when the body lacks a particular
enzyme to digest nutrients, nutrients are too abundant to be
completely digested, or a particular nutrient cannot be properly
digested, Common examples are lactose intolerance, FODPAM
intolerance, or lactulose intolerance (side effect of laxatives).
Food sensitivity, an understudied area, are immune-mediated
reaction to some nutrients and these reactions do not always
occur in the same way when eating that particular nutrient.
Food allergy is a very specific immune system response
involving either the immunoglobulin E (IgE) antibody or T-cells.
Both are immune system cells that react to a particular food
protein, such as milk protein.

Food sources of FODMAPs (where FODMAPs are
problematic based on standard serving size)
and suitable alternatives
FODMAP

Problem high FODMAP food
source

Suitable alternative lowFODMAP food source

Oligosaccharides (fructans
Polyols
and/or galactans)
Vegetables: artichokes,
Fruits: apples, pears, nashi
asparagus, beetroot, Brussels
Fruits: apples, apricots,
pears, clingstone peaches,
sprout, broccoli, cabbage,
cherries, longon, lychee, nashi
mango, sugar snap peas,
fennel, garlic, leeks, okra,
pears, nectarine, pears,
watermelon, tinned fruit in
onions, peas, shallots.
peaches, plums, prunes,
natural juice
Milk: cow, goat and sheep
watermelon
(regular & low-fat), Ice cream Cereals: wheat & rye when
Honey
eaten in large amounts (e.g.
Vegetables: avocado,
Yoghurt (regular & low-fat) bread, pasta, couscous,
cauliflower, mushrooms, snow
Sweeteners: fructose, high
crackers, biscuits)
peas
fructose corn syrup
Cheeses: soft & fresh (e.g.
ricotta, cottage)
Legumes: chickpeas, lentils, red
Sweeteners: sorbitol(420),
Large total fructose dose:
kidney beans, baked beans
mannitol(421), xylitol(967),
concentrated fruit sources;
maltitol (965), isomalt (953) &
large serves of fruit, dried fruit,
Fruits: watermelon, custard
others ending in '-ol'
fruit juice
apple, white peaches,
rambutan, persimmon
Fruit: banana, blueberry,
Vegetables: bamboo shoots,
carambola, durian, grapefruit,
Milk: lactose-free, rice milk bok choy, carrot, celery,
Fruits: banana, blueberry,
grape, honeydew melon,
capsicum, choko, choy sum,
carambola, durian, grapefruit,
kiwifruit, lemon, lime,
Cheese:'hard' cheeses
corn, eggplant, green beans,
grape, honeydew melon,
mandarin, orange,
including brie, camembert
lettuce, chives, parsnip,
kiwifruit, lemon, lime,
passionfruit, paw paw,
pumpkin, silverbeet, spring
mandarin, orange,
raspberry, rockmelon,
Yoghurt: lactose-free
onion (green only), tomato
passionfruit, paw paw,
strawberry, tangelo.
raspberry, rockmelon
Ice cream substitutes: gelati, Onion/garlic substitutes: garlicHoney substitutes: maple
sorbet
infused oil
Sweeteners: sugar (sucrose),
syrup, golden syrup
glucose, other artificial
Butter
Cereals: gluten-free & spelt
sweeteners not ending in 'ol'
Sweeteners: any except
bread/cereal products
polyols
Excess fructose

Lactose

Gibson PR, Sheperd SJ. J Gastroenterol Hepatol. 2010;25:252-258

Proposed New Classification of Gluten Related Disorders
Gluten Related
Disorders

Biomarkers

Pathogenesis

YES
Autoimmune

NO

Allergic

Not Autoimmune
Not allergic
(Innate immunity?)

YES
Celiac
Disease

Symptomitic

Gluten
Ataxia

Silent

Potential

Dermatitis
herpetiformis

Wheat
allergy

Respiratory
Allergy

Food
Allegy

Gluten
sensitivity

WDEIA

Contact
Urticaria

Differential Diagnosis Between CD, GS, and WA
Celiac Disease

Gluten Sensitivity

Wheat Allergy

Weeks-Years

Hours-Days

Minutes-Hours

Pathogenesis

Autoimmunity (Innate+
Adaptive Immunity)

Immunity?
(Iinnate Immunity?)

Allergic Immune Response

HLA

HLA DQ2/8 restricted
(~97% positive cases)

Not-HLA DQ2/8 restricted
(50% DQ2/8 positive cases)

Not-HLA DQ2/8 restricted
(35-40% positive cases as
in the general population)

Auto-antibodies

Almost always present

Always absent

Always absent

Enteropathy

Almost always present

Always absent
(slight increase in IEL)

Always absent
(eosinophils in the lamina
propria)

Symptoms

Both intestinal and
extra-intestinal (not
distinguishable from GS
and WA with GI
symptoms)

Both intestinal and extraintestinal (not
distinguishable from CD and
WA with GI symptoms)

Both intestinal and extraintestinal (not
distinguishable from CD
and GS when presenting
with GI symptoms)

Complications

Co-morbidities
Long term complications

Absence of co-morbidities
and long term complications
(long follow up studies
needed to confirm it)

Absence of co-morbidities.
Short-term complications
(incliuding anaphylaxis)

Time interval between
gluten exposure and
onset of symptoms

The Controversial Questions
About Gluten Sensitivity

Are The Epidemics Of Autism, ADHD and Schizophrenia
Also Related to The Rise of Non-Celiac Gluten Sensitivity?