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Celiac & Gluten Sensitivity

Scot Michael Lewey, DO, FACG, FASGE, AGAF, FACOI, FACP, FAAP, FACOP
Gastroenterologist
Peak G...
Differential Diagnosis of Abdominal Pain, Diarrhea &
Bloating
•

•

•
•

•

Inflammatory Bowel Disease (IBD)
– Ulcerative ...
What is Celiac disease?

• Abnormal small intestine lining from injury
• Injury is result of gluten induced inflammation
•...
What is Gluten
• 10-15% extractable protein portion of
wheat
• Subdivided into gliadin & glutenin
– Gliadin 15,000 molecul...
What is gluten sensitive enteropathy?
• Protein gluten in wheat, rye, & barley, +/oats injures sensitive small intestine
•...
What happens in Celiac disease?
• Proteins in wheat, rye, barley resistant to
digestion in stomach and by pancreatic
enzym...
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Autoimmune gut inflammation in Celiac
disease
• “B lymphocytes” white blood cells produce
IgA & IgG class antibodies again...
Who gets Celiac, Whose at Risk?
• Genetic predisposition
– HLA DQ2, DQ8 in >90%

• Sometimes occurs after trigger such as
...
How common is Celiac Disease?
• More common than previously thought
• 1% or 1/100 of general population
– 3 million Americ...
“Iceberg hidden epidemic” of Celiac
disease & non-celiac gluten sensitivity
•1% worldwide have Celiac disease by specific
...
Clues that celiac should be
considered-screen

Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology
Celiac is frequently missed by primary care physicians
Primary Care Physician Awareness

Percentage

Wheat intolerance
Ons...
Celiac & IBS Link Recognized
Increasingly

Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associ...
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology
•

•

•

•

•

Historically, it has been reported that patients with undetected celiac
disease (CD) may present with irrit...
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Popularity of Gluten Sensitivity
& Celiac online

Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology...
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
HLA Genetics
• All of us have “white blood cell types” based on
inherited HLA genes Just like we have a red
blood cell typ...
Prevalence of potentially gluten sensitive HLA
DQ genes

HLA DQ TYPE

PREVALENCE

HLA DQ2

31%

HLA DQ8

12%

HLA DQ1,7

1...
How does gluten trigger autoimmune celiac disease?

• Fractions of gluten proteins in
intestine get through intestinal
bar...
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Ancient & Early Celiac History
• Aretaeus of
Cappadocia 250 A.D.
• Described “koiliakos”
which meant “suffering in
the bow...
Dr. Samuel Gee
• 1888 Dr. Samuel Gee of the
Great Ormond Street Hospital
for Children in the U.K.
• Published “On the Coel...
Dr Hass & the “Banana Diet”
• 1924 NY Pediatrician Sidney Valentine Haas
described treatment banana diet, excluded bread,
...
Dr. Dicke linked gluten to Celiac
• Dutch pediatrician Willem K.
Dicke Netherlands suspected
grain as cause
• During WWII ...
Celiac History- Role of Intestinal Biopsy
• 1954 Pauley reported abnormal
appearance of jejunal mucosa obtained
at operati...
Elaine Gottschall & SCD
• Elaine Gottschall
housewife with
daughter with IBD
“cured”
• Becomes PhD
• Publishes “Breaking
t...
History of the Celiac Blood Tests
• 1971 reticulin antibodies described,
specific but not sensitive
• Gliadin antibodies
•...
How is Celiac Sprue diagnosed?
 Positive specific blood test
 Tissue transglutaminase antibody (tTG)
 Endomysial antibo...
Celiac Blood Tests
 IgA endomysial antibody (IgA EMA)
 IgA tissue transglutaminase antibody (IgA tTG)
 Positive >90% of...
Endomysial IgA antibody (EMA)
 Bind to endomysium, connective tissue
around smooth muscle
 Produces a characteristic sta...
Anti-Tissue transglutaminase antibodies (tTG)
• Enzyme present throughout body (brain, skin,
and intestine)
 Antigen dire...
“Non-specific” Celiac Tests
• Antigliadin antibodies (AGA) more sensitive
detecting gluten sensitivity
• AGA used to monit...
Natural History of Positive Endomysial Antibody
(EMA) With Normal Duodenal Biopsy

• 96% who tried GFD improved
• 88% on n...
“Normal biopsies” do not
exclude Celiac disease
• Positive endomysial antibody
with “normal” biopsy but
abnormal immuhisto...
Seronegative Celiac Disease
Celiac disease with negative blood tests

• Celiac disease
• 71% total villous atrophy (TVA)
•...
Celiac Disease Villous Atrophy

Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Scalloped Folds & Mosaic Mucosal
Pattern

Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associa...
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Celiac Specific Blood Tests
 IgA endomysial antibody (IgA EMA)
 IgA tissue transglutaminase antibody (IgA
tTG)
 Positiv...
Celiac Specific Blood Tests
• IgA endomysial antibody (IgA EMA)
• IgA tissue transglutaminase antibody (IgA
tTG)
• Positiv...
Definitive Diagnosis of Celiac
Disease
•
•
•
•
•

Concordant positive serology + biopsy
Presumptive diagnosis made
Gluten-...
What about patient started glutenfree diet without testing?
• Cannot confirm or exclude diagnosis
• Recommend gluten-chall...
Further Diagnosis
• Normal biopsy after gluten
avoidance
• Symptoms & abnormal biopsy
return with gluten challenge
• HLA D...
History of the Small Bowel
Biopsy
1954 Pauley reported abnormal
appearance of jejunal mucosa
obtained at operation
Shine...
Close-up of Crosby Capsule

Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
X-ray of Crosby-Kugler Capsule

Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Assessing Duodenal Biopsies

Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Celiac disease pathology

Normal slender finger like villi
3-5:1 villous to crypt ratio
No increased intraepithelial lymph...
Celiac Disease-Subtotal Villous
Atrophy

Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associat...
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Intraepithelial Lymphocytosis
“Marsh I Lesion”

• Immune active white blood cells (lymphocytes)
are normally present in vi...
Intraepithelial Lymphocytosis
“Marsh I Lesion”

• Increased lymphocytes or IEL’s in tips of villi is
highly suggestive of ...
Immunohistochemical staining
makes it easier to see early changes
• Immune staining
using antibodies that
are specific for...
Immunohistochemical
staining
• Stains are very accurate
• Reproducible
• Reduces subjective
reading error.

• But these st...
Normal biopsies may not be
normal

• Pathologists reading the intestinal
biopsies have varying degree of
experience

• The...
Normal biopsies may not be
normal
• Pathologists reading the intestinal
biopsies have varying degree of
experience
• They ...
Electron Microscopy of Villi

 Electron microscopy abnormalities may be
seen on intestine biopsies when biopsy
appears no...
“Normal biopsies” not always
normal
• People with a positive celiac blood test positive
had a “normal” biopsies have been ...
Conclusions
• Biopsies can confirm Celiac disease type
changes and assess their severity.
• Biopsies may suggest Celiac di...
Routine biopsies of duodenum strongly encouraged
Prevalence of Celiac disease is 1% in general population but much higher ...
4 biopsies should be done of
duodenum

Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology
No excuse for failure to obtain
duodenal biopsies

Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterolog...
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology
What about patient started glutenfree diet without testing?
• Cannot confirm or exclude diagnosis
• Recommend gluten-chall...
Non-Celiac gluten sensitivity diarrhea
reverses with gluten free diet
• Girls with chronic severe diarrhea
• Explosive wat...
Non-celiac gluten sensitivity (NCGS)
• Duodenal biopsies “normal” except
intraepithelial lymphocytes
• However, with glute...
Elevated stool gliadin antibodies
Population (Number)

Positivity Rate (%)

Untreated Celiac (20)

100%

Microscopic colit...
The “iceberg” or “hidden epidemic”
of Non-Celiac gluten sensitivity
• >60% those tested had one of HLA DQ
types predisposi...
Old belief = Celiac disease

New paradigm gluten sensitive

Celiac disease is rare
1/2000-5000 people world wide

Celiac d...
New Paradigm: Gluten sensitivity not just a gut disease
• Gluten Sensitivity, Celiac Disease, & Celiac Sprue
used synonymo...
Diagnosis and classification of celiac disease and gluten sensitivity.
Autoimmun Rev 2014
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Celiac disease is...
How is Celiac treated?
• Lifelong gluten free diet
• Exclude wheat, rye, & barley
• Oats safe in most but cross
contaminat...
New Paradigm: Gluten Sensitivity Is
Not Just a Disease of the Gut
“the systemic nature of this disease, the
overwhelming e...
CONCLUSIONS
Regarding Celiac Disease
• Celiac disease is common but non-celiac
gluten sensitivity is much more common
• Th...
CONCLUSIONS
Regarding Non-Celiac Gluten
Sensitivity
• Abnormal gliadin antibodies or non-specific blood
tests likely indic...
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Copyright (c) 2014 Scot M.
Lewey, DO, FACP, FACG - Peak
Gastroenterology Associates,
Gliadin does not induce mucosal inflammation or basophil activation in patients with
nonceliac gluten sensitivity. Clin. G...
Non-coeliac gluten sensitivity: hype, or new epidemic?
Ned Tijdschr Geneeskd 2013 (21)
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Coeliac disease is a...
Prevalence of gluten-free diet adherence among individuals without celiac disease in the
USA: results from the Continuous ...
Non-celiac gluten sensitivity: questions still to be answered despite
increasing awareness
Cell. Mol. Immunol. 2013
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•

...
Mucosal cytokine response after short-term gluten challenge in celiac disease and
non-celiac gluten sensitivity.Am. J. Gas...
Non-celiac gluten sensitivity: clinical relevance and
recommendations for future research.
Neurogastroenterol. Motil. 2013...
Is gluten a cause of gastrointestinal symptoms in people without
celiac disease?
Curr Allergy Asthma Rep 2013
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Non-Celiac Gluten sensitivity: the new frontier of gluten related
disorders.
Nutrients 2013
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Celiac Glute...
A UK study assessing the population prevalence of self-reported
gluten sensitivity and referral characteristics to seconda...
Clinical, Serologic, and Histologic Features of Gluten Sensitivity in Children.
J. Pediatr. 2013
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Study ...
Seroreactive marker for inflammatory bowel disease and associations with
antibodies to dietary proteins in bipolar disorde...
Reactivity to dietary gluten: new insights into differential diagnosis
among gluten-related gastrointestinal disorders.
Po...
Biomarkers of gluten sensitivity in patients with non-affective
psychosis: A meta-analysis.
Schizophr. Res. 2013
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Non-celiac gluten sensitivity. Is it in the gluten or the grain?
J Gastrointestin Liver Dis 2013
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Celiac d...
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Leonardo da Vinci's face symmetry derives from 3 equal craniofacial segments
It has been reported that ...
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Food intolerance is a common complaint amongst patients with functional
gastrointestinal (GI) disorde...
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Celiac Disease, Gluten Sensitivity_Dr. Scot Lewey

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Dr. Scot M. Lewey, DO, FACG, FACP - CELIAC and GLUTEN SENSITIVITY_CME PRESENTATION-ACCREDITED MATERIAL_COPYRIGHT (C) 2014 SCOT M LEWEY

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Transcript of "Celiac Disease, Gluten Sensitivity_Dr. Scot Lewey"

  1. 1. Celiac & Gluten Sensitivity Scot Michael Lewey, DO, FACG, FASGE, AGAF, FACOI, FACP, FAAP, FACOP Gastroenterologist Peak Gastroenterology Associates Clinical Professor of Medicine Rocky Vista University-College of Osteopathic Medicine & Kansas City University of Medicine and Bioscience www.thefooddoc.com www.peakgastro.com @thefoodgutdoc Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Facebook.com/thefooddoc Gastroenterology Associates,
  2. 2. Differential Diagnosis of Abdominal Pain, Diarrhea & Bloating • • • • • Inflammatory Bowel Disease (IBD) – Ulcerative Colitis (UC), Crohn’s Disease (CD), Diverticular Associated Colitis (DAC) – Microscopic Colitides • Lymphocytic Colitis (LC), Collagenous Colitis (CC), & Mastocytic Enterocolitis (MCE) Celiac Disease-Celiac Sprue (CS) – Non-Celiac Gluten Sensitivity (NCGS) Diarrhea Predominant Irritable Bowel Syndrome (IBS-D) Carbohydrate Intolerances – Lactose Intolerance (LI) – Fructose Intolerance (FI) Dysbiosis/Altered Gut Flora Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  3. 3. What is Celiac disease? • Abnormal small intestine lining from injury • Injury is result of gluten induced inflammation • It is an autoimmune reaction with common triggers • The risk is genetically inherited • Malabsorption occurs as a Scot M. result Copyright (c) 2014 Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  4. 4. What is Gluten • 10-15% extractable protein portion of wheat • Subdivided into gliadin & glutenin – Gliadin 15,000 molecular weight – Active factor in small bowel injury – Fraction 3, <1,000 mw sub-fraction Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  5. 5. What is gluten sensitive enteropathy? • Protein gluten in wheat, rye, & barley, +/oats injures sensitive small intestine • Chronic small intestine injury =enteropathy • Injured small intestine = malabsorption • Abnormal immune system reaction results in extra-intestinal symptoms & signs • Intestinal injury & symptoms resolve with gluten-free diet (c) 2014 Scot M. Copyright Lewey, DO, FACP, FACG - Peak Gastroenterology
  6. 6. What happens in Celiac disease? • Proteins in wheat, rye, barley resistant to digestion in stomach and by pancreatic enzymes • Make way into lining, possibly pre-injured by infection, predisposed by genetic HLA type • Activate T lymphocytes that release chemicals (cytokines) causing inflammation & damage • Damaged lining malabsorbs nutrients & vulnerable to more injury Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  7. 7. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  8. 8. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  9. 9. Autoimmune gut inflammation in Celiac disease • “B lymphocytes” white blood cells produce IgA & IgG class antibodies against tTG, endomysium (EMA), & gliadin • Increase T-lymphocytes recruited (intraepithelial lymphocytosis) and chemicals released damage occurs to intestinal villi (atrophy/blunting) further increasing leaky gut Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  10. 10. Who gets Celiac, Whose at Risk? • Genetic predisposition – HLA DQ2, DQ8 in >90% • Sometimes occurs after trigger such as surgery, pregnancy, childbirth, viral infection, emotional stress • Breast feeding appears to be protective • Age at which & how much gluten introduced may affect Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  11. 11. How common is Celiac Disease? • More common than previously thought • 1% or 1/100 of general population – 3 million Americans may be affected • Several European studies 1/152 to 1/300 in Ireland, UK, Italy & Sweden • US blood donor screening 1/133-1/250 compared to previous 1/6000 estimated prevalence of Celiac disease Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  12. 12. “Iceberg hidden epidemic” of Celiac disease & non-celiac gluten sensitivity •1% worldwide have Celiac disease by specific serology testing (EMA or tTG) •Up to 12% of population is gluten sensitive (GS) by serology testing “not specific” for Celiac disease •40% of U.S. HLA DQ2 or DQ8+, the major genes predisposing to CD Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  13. 13. Clues that celiac should be considered-screen Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  14. 14. Celiac is frequently missed by primary care physicians Primary Care Physician Awareness Percentage Wheat intolerance Onset of symptoms in adults existed 95% 32% Diarrhea as a symptom IBS symptoms are common Chronic abdominal pain common Fatigue is common Depression & irritability common Associated with diabetes Associated with anemia Associated with osteoporosis Diagnosed by blood tests 90% 71% 67% 54% 24% 13% 45% 45% 44% Copyright (c) Med. 2005; Zipser et.al J Gen Intern 2014 Scot M. 20(7):644-6 Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  15. 15. Celiac & IBS Link Recognized Increasingly Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  16. 16. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  17. 17. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  18. 18. • • • • • Historically, it has been reported that patients with undetected celiac disease (CD) may present with irritable bowel syndrome (IBS) type symptoms. This has led to the recommendation by the American College of Gastroenterology Task force that patients presenting with diarrhea predominant IBS type symptoms should be serologically tested for CD. Concurrently speculative media data suggest that the US general public have increased their uptake of a gluten-free diet (GFD) far in excess of the known prevalence of CD. This may suggest that individuals with gastrointestinal symptoms are deriving benefit from a GFD even if they do not have CD. This has led to the scientific community considering the evidence for an emerging concept of non-celiac wheat sensitivity. There is a significant disparity in our views about what this phenomenon may be. There is also confusion about the nomenclature for this entity and indeed whether patients are suffering due to symptoms related to gluten or perhaps other components of wheat, for example fructans….we see evidence to support the clinical concept of wheat sensitivity or intolerance.. Am. J. Gastroenterol. 2012 (12):1908-12 Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  19. 19. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  20. 20. Popularity of Gluten Sensitivity & Celiac online Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  21. 21. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  22. 22. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  23. 23. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  24. 24. HLA Genetics • All of us have “white blood cell types” based on inherited HLA genes Just like we have a red blood cell types (I’m A positive) we have white blood cell types (I’m DQ2/DQ7) • Our HLA “white blood cell types” are inherited • Our HLA protein types determine our risk for certain diseases, especially autoimmune diseases like Celiac disease & type I Diabetes Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  25. 25. Prevalence of potentially gluten sensitive HLA DQ genes HLA DQ TYPE PREVALENCE HLA DQ2 31% HLA DQ8 12% HLA DQ1,7 18% HLA DQ1,9 1% Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  26. 26. How does gluten trigger autoimmune celiac disease? • Fractions of gluten proteins in intestine get through intestinal barrier (leaky gut) • Tissue transglutamidase type 2 (tTG) enzyme converts gluten to toxic gliadin fragments • These toxic gliadin proteins interact with white blood cells via surface HLA DQ2 &/or DQ8 protein molecules Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  27. 27. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  28. 28. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  29. 29. Ancient & Early Celiac History • Aretaeus of Cappadocia 250 A.D. • Described “koiliakos” which meant “suffering in the bowels” • Francis Adams translated Aretaeus observations from Greek to English for the Sydenham Society of England in 1856 • “Koiliakos” became Celiac or Coeliac Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  30. 30. Dr. Samuel Gee • 1888 Dr. Samuel Gee of the Great Ormond Street Hospital for Children in the U.K. • Published “On the Coelic Affliction” • Recognized dietary cause but mistakenly advised gluten containing foods • Presented accounts of both children & adults with Coeliac • “to regulate food is the main part of treatment. The allowance of farinaceous foods must be small, but if the patient can be cured at all, it must be by means of diet” Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  31. 31. Dr Hass & the “Banana Diet” • 1924 NY Pediatrician Sidney Valentine Haas described treatment banana diet, excluded bread, crackers, potatoes & cereals, later published “The Management of Celiac Disease” in 1951 • Described cures of Celiac with diet • Led to many individuals now with untreated Celiac Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  32. 32. Dr. Dicke linked gluten to Celiac • Dutch pediatrician Willem K. Dicke Netherlands suspected grain as cause • During WWII scarcity of cereals & breads & noted Celiac Sprue diminished remarkably during this shortage • Observed relapse after air lift bread by Swedish planes into Netherlands • He then found that alcohol soluble fraction of wheat gluten known as gliadin was toxic portion of wheat • Published his thesis Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  33. 33. Celiac History- Role of Intestinal Biopsy • 1954 Pauley reported abnormal appearance of jejunal mucosa obtained at operation • Shiner & Royal independently developed biopsy method • Crosby developed suction capsule “Crosby capsule” swallowed by Copyright (c) 2014 Scot M. patients Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  34. 34. Elaine Gottschall & SCD • Elaine Gottschall housewife with daughter with IBD “cured” • Becomes PhD • Publishes “Breaking the Vicious Cycle” • Specific Carbohydrate Diet “SCD” Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  35. 35. History of the Celiac Blood Tests • 1971 reticulin antibodies described, specific but not sensitive • Gliadin antibodies • Endomysial antibodies • 1997 tissue transglutaminase antibody (tTG) established as autoantigen for endomysial antibody • HLA DQ genetic testing in past several years Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  36. 36. How is Celiac Sprue diagnosed?  Positive specific blood test  Tissue transglutaminase antibody (tTG)  Endomysial antibody (EMA)  Serology less reliable < 5 yr old age  Abnormal biopsy of small bowel  Villous blunting/atrophy, crypt hyperplasia, intraepithelial lymphocytes  Patchy distribution, multiple biopsies needed  Symptom improvement on a gluten-free diet & normalization of serologies and/or biopsy Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  37. 37. Celiac Blood Tests  IgA endomysial antibody (IgA EMA)  IgA tissue transglutaminase antibody (IgA tTG)  Positive >90% of untreated Celiacs  Can be negative in mild disease, IgA deficient, immunosuppressives  Rarely positive in non-Celiacs  Since 10% Celiac are IgA deficient tests could be negative in those individuals  IgG antigliadin more sensitive in this setting but accused on having high false positive  “Normal” individuals, probably NCGS/latent Celiacs; cow’s milk allergy and post-viral enteritis Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  38. 38. Endomysial IgA antibody (EMA)  Bind to endomysium, connective tissue around smooth muscle  Produces a characteristic staining pattern seen under immunofluorescence  Simply reported as either positive or negative  If positive, considered diagnostic  May be misinterpreted by some labs Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  39. 39. Anti-Tissue transglutaminase antibodies (tTG) • Enzyme present throughout body (brain, skin, and intestine)  Antigen directed against EMA  Positive in setting of characteristic biopsy is definitive for Celiac  Falsely negative when IgA deficient (10-20% of Celiac disease patients)  Only positive in 40%, usually negative in early or mild celiac Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  40. 40. “Non-specific” Celiac Tests • Antigliadin antibodies (AGA) more sensitive detecting gluten sensitivity • AGA used to monitor compliance or hidden exposure • Becomes positive early and stays positive later • Increased sensitivity of IgG antigliadin accused of high false positives – Reportedly positive in “normal” individuals, cow’s milk allergy, post-viral infection, Crohn’s disease • More likely reflects non-Celiac gluten sensitive individuals and early Celiac Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  41. 41. Natural History of Positive Endomysial Antibody (EMA) With Normal Duodenal Biopsy • 96% who tried GFD improved • 88% on normal diet developed villous atrophy on follow-up biopsies • Positive (EMA) indicates gluten sensitivity, even if biopsy is normal • Positive EMA is not a false positive test Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  42. 42. “Normal biopsies” do not exclude Celiac disease • Positive endomysial antibody with “normal” biopsy but abnormal immuhistochemistry stains • All became EMA negative on gluten free diet who tried GFD Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  43. 43. Seronegative Celiac Disease Celiac disease with negative blood tests • Celiac disease • 71% total villous atrophy (TVA) • 29% had partial villous atrophy (PVA) • 67% with PVA had a negative EMA • 23% with TVA had a negative EMA • You can be a Celiac with NEGATIVE EMA blood test! • Abrams et.al. Dig Dis Sci. 2004 Apr;49(4):546-50 Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  44. 44. Celiac Disease Villous Atrophy Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  45. 45. Scalloped Folds & Mosaic Mucosal Pattern Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  46. 46. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  47. 47. Celiac Specific Blood Tests  IgA endomysial antibody (IgA EMA)  IgA tissue transglutaminase antibody (IgA tTG)  Positive >90% of untreated Celiacs Can be negative in mild disease, Can be negative in IgA deficient or immunosuppressived Rarely positive in non-Celiacs EMA negative reported that are severe, more likely men, and higher risk of lymphoma Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  48. 48. Celiac Specific Blood Tests • IgA endomysial antibody (IgA EMA) • IgA tissue transglutaminase antibody (IgA tTG) • Positive >90% of untreated Celiacs – Can be negative in mild disease, IgA deficient, immunosuppressives • Rarely positive in non-Celiacs • Since % Celiac are IgA deficient tests could be negative in those individuals • IgG antigliadin more sensitive in this setting but high false positive – Normal individuals, cow’s milk allergy, post-viral Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  49. 49. Definitive Diagnosis of Celiac Disease • • • • • Concordant positive serology + biopsy Presumptive diagnosis made Gluten-free diet started Symptoms resolve Normalization of biopsy no longer required for definitive diagnosis though supports • Older standard required challenge with documentation of return symptoms and abnormal biopsy Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  50. 50. What about patient started glutenfree diet without testing? • Cannot confirm or exclude diagnosis • Recommend gluten-challenge followed by – Serologic testing • If positive, then biopsy to confirm diagnosis • If negative or individual declines to undergo gluten challenge then HLA DQ2, DQ8 testing an option – If negative, extremely unlikely Celiac – If positive, as already noted, repeat serology and/or biopsy after additional interval on gluten containing diet • Resolution of symptoms on gluten-free diet not sufficient to diagnose Celiac, though no adverse nutritional effects from careful gluten-free diet Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  51. 51. Further Diagnosis • Normal biopsy after gluten avoidance • Symptoms & abnormal biopsy return with gluten challenge • HLA DQ2 &/or HLA DQ8 positive supportive Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  52. 52. History of the Small Bowel Biopsy 1954 Pauley reported abnormal appearance of jejunal mucosa obtained at operation Shiner & Royal independently developed biopsy method Crosby developed suction capsule “Crosby capsule” swallowed by patients Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  53. 53. Close-up of Crosby Capsule Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  54. 54. X-ray of Crosby-Kugler Capsule Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  55. 55. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  56. 56. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  57. 57. Assessing Duodenal Biopsies Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  58. 58. Celiac disease pathology Normal slender finger like villi 3-5:1 villous to crypt ratio No increased intraepithelial lymphocytes Abnormal is blunted to flat, villous to crypt ratio <3:1, increased IELs Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  59. 59. Celiac Disease-Subtotal Villous Atrophy Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  60. 60. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  61. 61. Intraepithelial Lymphocytosis “Marsh I Lesion” • Immune active white blood cells (lymphocytes) are normally present in villi but not excessively in tips • Increased numbers of lymphocytes or IEL’s with normal villi is earliest abnormality with gluten challenge Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  62. 62. Intraepithelial Lymphocytosis “Marsh I Lesion” • Increased lymphocytes or IEL’s in tips of villi is highly suggestive of gluten sensitivity • But may also be seen in other conditions like giardiasis, H. pylori infection, cow’s milk protein allergy (CMPA) or intolerance (CMPI) Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  63. 63. Immunohistochemical staining makes it easier to see early changes • Immune staining using antibodies that are specific for the lymphocytes cells makes it easier to see and count numbers of IEL’s • Increased IEL’s in villous tip show up as reddish brown cells Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  64. 64. Immunohistochemical staining • Stains are very accurate • Reproducible • Reduces subjective reading error. • But these stains are not routinely performed and have to be requested. This can be important in early Celiac disease or in those who have already restricted gluten in their diet. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  65. 65. Normal biopsies may not be normal • Pathologists reading the intestinal biopsies have varying degree of experience • They also may have a negative bias towards “over diagnosing” Celiac disease Biopsies that are “normal” under routine light microscope have been shown to be abnormal when examined with special stains and research based Copyright (c) 2014 Scot M. electron microscopyFACG - Peak Lewey, DO, FACP, Gastroenterology Associates,
  66. 66. Normal biopsies may not be normal • Pathologists reading the intestinal biopsies have varying degree of experience • They also may have a negative bias towards “over diagnosing” Celiac disease • Biopsies that are “normal” under routine light microscope have been shown to be abnormal when examined with (c) 2014 Scot M. special stainsCopyrightFACP, FACG - Peakbased and research Lewey, DO, electron microscopy Gastroenterology
  67. 67. Electron Microscopy of Villi  Electron microscopy abnormalities may be seen on intestine biopsies when biopsy appears normal  Gluten injury may be (c) 2014 Scot M. when biopsy Copyright present Lewey, DO, FACP, FACG appears normal Gastroenterology - Peak
  68. 68. “Normal biopsies” not always normal • People with a positive celiac blood test positive had a “normal” biopsies have been studied using research electron microscopy (EM) • Majority have abnormal electron microscopy studies of biopsies • Therefore normal biopsies may not be normal and do not exclude Celiac disease especially when blood tests are positive Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  69. 69. Conclusions • Biopsies can confirm Celiac disease type changes and assess their severity. • Biopsies may suggest Celiac disease by early changes that may only be seen on special stains especially if gluten has been restricted. • Biopsies may reveal another diagnosis or abnormality not otherwise detectable without a biopsy. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  70. 70. Routine biopsies of duodenum strongly encouraged Prevalence of Celiac disease is 1% in general population but much higher in patients presenting for EGD for symptoms Histological changes may be present with “normal” appearing mucosa or subtle mucosal abnormalities not appreciated by endoscopist Duodenal biopsy rates during EGD varied from 30%-74% per CORI Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  71. 71. 4 biopsies should be done of duodenum Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  72. 72. No excuse for failure to obtain duodenal biopsies Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  73. 73. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  74. 74. What about patient started glutenfree diet without testing? • Cannot confirm or exclude diagnosis • Recommend gluten-challenge followed by – Serologic testing • If positive, then biopsy to confirm diagnosis • If negative or individual declines to undergo gluten challenge then HLA DQ2, DQ8 testing an option – If negative, extremely unlikely Celiac – If positive, as already noted, repeat serology and/or biopsy after additional interval on gluten containing diet • Resolution of symptoms on gluten-free diet not sufficient to diagnose Celiac, though no adverse nutritional effects from careful gluten-free diet Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  75. 75. Non-Celiac gluten sensitivity diarrhea reverses with gluten free diet • Girls with chronic severe diarrhea • Explosive watery diarrhea also occurring at night • Symptoms included loss of appetite, malaise, weight loss & abdominal pain • Normal blood tests • Duodenal biopsies: “normal” except intra-epithelial lymphocytes • Therefore were note Celiac Disease using strict criteria for diagnosis Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  76. 76. Non-celiac gluten sensitivity (NCGS) • Duodenal biopsies “normal” except intraepithelial lymphocytes • However, with gluten-free diet chronic diarrhea resolved • Increased IEL’s resolved • Gluten challenge & diarrhea recurred • Gluten causes inflammation of gut that causes of diarrhea even if biopsy “normal” or non-diagnostic and blood tests are normal • NCGS exists Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  77. 77. Elevated stool gliadin antibodies Population (Number) Positivity Rate (%) Untreated Celiac (20) 100% Microscopic colitis (63) 75% Chronic diarrhea (182) 49% Normal (37) 32% “Symptomatic” (14) 57% Treated Celiacs (11) 9% Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  78. 78. The “iceberg” or “hidden epidemic” of Non-Celiac gluten sensitivity • >60% those tested had one of HLA DQ types predisposing to gluten sensitivity • All untreated Celiacs had elevated stool antibodies to gluten • >50% of high risk & symptomatic individuals had elevated stool AGA IgA with or without + fecal tTG IgA) • 35% of normal individuals tested had elevated stool antibodies to gluten Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  79. 79. Old belief = Celiac disease New paradigm gluten sensitive Celiac disease is rare 1/2000-5000 people world wide Celiac disease common 1/100 1/3 to 1/10 gluten sensitivity EMA or tTG specific Celiac blood tests positive 1/250 to 1/100 1/8 positive blood gliadin 1/3 positive stool gliadin +/- tTG Duodenal biopsy is “gold standard” for diagnosis Biopsy not gold standard Increase IELs, EM studies 95-99% Celiac disease are DQ2 &/or DQ8 positive 1/1.6 DQ risk for gluten sensitivity Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  80. 80. New Paradigm: Gluten sensitivity not just a gut disease • Gluten Sensitivity, Celiac Disease, & Celiac Sprue used synonymously for years but to quote Hadjivassiliou in 2004: • “the systemic nature of this disease, the overwhelming evidence of an immune pathogenesis and the accumulating evidence of diverse manifestations involving organs other than the gut, such as the skin (dermatitis herpetiformis) and the nervous system (gluten ataxia, gluten neuropathy), necessitates a re-evaluation of the belief that gluten sensitivity is solely a disease of the gut.” • Hadjivassiliou et.al. in Trends in Immunology 2004 Nov; 25(11):578-582 Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  81. 81. Diagnosis and classification of celiac disease and gluten sensitivity. Autoimmun Rev 2014 • • • • • • Celiac disease is a complex disorder, the development of which is controlled by a combination of genetic (HLA alleles) and environmental (gluten ingestion) factors. New diagnostic guidelines developed by ESPGHAN emphasize the crucial role of serological tests in the diagnostic process of symptomatic subjects, and of the detection of HLA DQ2/DQ8 alleles in defining a diagnosis in asymptomatic subjects belonging to at-risk groups. The serological diagnosis of CD is based on the detection of class IgA anti-tissue transglutaminase (anti-tTG) and anti-endomysial antibodies. In patients with IgA deficiency, anti-tTG or anti-deamidated gliadin peptide antibody assays of the IgG class are used. When anti-tTG antibody levels are very high, antibody specificity is absolute and CD can be diagnosed without performing a duodenum biopsy. Non-celiac gluten sensitivity is a gluten reaction in which both allergic and autoimmune mechanisms have been ruled out. Diagnostic criteria for NCGS include the presence of symptoms similar to those of celiac or allergic patients; negative allergological tests and absence of anti-tTG and EMA antibodies; normal duodenal histology; evidence of disappearance of the symptoms with a gluten-free diet; relapse of the symptoms when gluten is reintroduced. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  82. 82. How is Celiac treated? • Lifelong gluten free diet • Exclude wheat, rye, & barley • Oats safe in most but cross contamination • 70% with symptoms @ diagnosis notice improvement in intestinal symptoms within 2 weeks of beginning gluten-free diet • Even small amounts of gluten can cause disease & symptoms Scot M. Copyright (c) 2014 Lewey, DO, FACP, FACG - Peak Gastroenterology
  83. 83. New Paradigm: Gluten Sensitivity Is Not Just a Disease of the Gut “the systemic nature of this disease, the overwhelming evidence of an immune pathogenesis and the accumulating evidence of diverse manifestations involving organs other than the gut, such as the skin (dermatitis herpetiformis) and the nervous system (gluten ataxia, gluten neuropathy), necessitates a re-evaluation of the belief that gluten sensitivity is solely a disease of the gut.” Dr. M Hadjivassiliou, 2004 Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  84. 84. CONCLUSIONS Regarding Celiac Disease • Celiac disease is common but non-celiac gluten sensitivity is much more common • Though abnormal specific blood tests and an abnormal biopsy can confirm celiac disease, normal biopsies neither exclude celiac nor gluten sensitivity • Abnormal specific blood tests likely confirm celiac disease even if biopsy is “normal” Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  85. 85. CONCLUSIONS Regarding Non-Celiac Gluten Sensitivity • Abnormal gliadin antibodies or non-specific blood tests likely indicate gluten sensitivity • Elevated gliadin antibodies may be earliest sign of celiac disease before specific blood tests or biopsy are abnormal • Symptoms that respond to a gluten-free diet indicate gluten sensitivity • The presence of stool gliadin antibodies predict response to gluten free diet and support diagnosis of non-celiac gluten sensitivity Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  86. 86. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  87. 87. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  88. 88. Gliadin does not induce mucosal inflammation or basophil activation in patients with nonceliac gluten sensitivity. Clin. Gastroenterol. Hepatol. 2013 • • • • • • • • • Nonceliac gluten-sensitive (NCGS) patients report intestinal and extra-intestinal symptoms shortly after ingesting gluten; these symptoms disappear on gluten-free diets, although these patients have no serologic markers of celiac disease or intestinal damage. There is no evidence for mucosal or serologic modifications in those individuals. Investigation of immunologic responses of duodenal mucosa samples and peripheral blood basophils, isolated from NCGS patients, after exposure to gliadin. Participants underwent a complete clinical evaluation to exclude celiac disease while on a gluten-containing diet, a skin prick test to exclude wheat allergy, and upper endoscopy (n = 119) at 2 tertiary medical centers in Italy. Patients were considered to have NCGS based on their symptoms and the current definition of the disorder. Subjects were assigned to the following groups: patients with celiac disease on gluten-free diets (n = 34), untreated patients with celiac disease (n = 35), patients with NCGS (n = 16), or controls (n = 34) Duodenal mucosa samples collected from 69 patients with celiac disease showed markers of inflammation after incubation with gliadin. Some, but not all, markers of inflammation were detected weakly in biopsy samples from 3 controls and 3 NCGS patients (P = .00 for all markers). There were no significant increases in the levels of CD63 and CD203c in NCGS patients. Unlike the duodenal mucosa from patients with celiac disease, upon incubation with gliadin, mucosa from patients with NCGS does not express markers of inflammation, and their basophils are not activated by gliadin. In vitro gliadin challenge therefore should not be used to diagnose NCGS. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  89. 89. Non-coeliac gluten sensitivity: hype, or new epidemic? Ned Tijdschr Geneeskd 2013 (21) • • • • • Coeliac disease is an immune-mediated inflammation of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically sensitive individuals. Recently, a novel gluten-related disorder has gained significant interest from the scientific community and mass media. This condition, known as non-coeliac gluten sensitivity, is characterised by gastrointestinal or extra-intestinal symptoms that respond to gluten withdrawal without evidence of underlying coeliac disease. Its symptoms overlap considerably with those of irritable bowel syndrome and the number of individuals embracing a gluten-free diet is rapidly growing. No discriminative markers to support a diagnosis of gluten sensitivity have been identified; the perceived response to a gluten-free diet after exclusion of coeliac disease is currently the best diagnostic and therapeutic marker. Its pathogenesis remains obscure but may be related to non-gliadin molecules in grains that stimulate the innate immune system of the Copyright (c) 2014 Scot M. intestine. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  90. 90. Prevalence of gluten-free diet adherence among individuals without celiac disease in the USA: results from the Continuous National Health and Nutrition Examination Survey 2009-2010 Scand. J. Gastroenterol. 2013 • • • • • • • • Clinical inference suggests the prevalence of non-celiac gluten sensitivity is substantially higher than that of celiac disease in the USA. Unfortunately, there are currently no data supporting these claims. The authors analyzed nationally representative data to estimate the prevalence of adherence to a gluten-free diet among participants without celiac disease and also to characterize the demographics and general health status of these participants. The Continuous National Health and Nutrition Examination Survey (NHANES) 2009-2010 enrolled 7762 individuals representing the civilian, non-institutionalized, US population free of celiac disease. Participants responded to interviewer administered questionnaires regarding current adherence to a gluten-free diet. Prevalence estimates were computed using SAS survey procedures. There were 49 individuals who reported current adherence to a gluten-free diet reflecting a weighted prevalence of 0.548% (95% CI 0.206-0.889). The prevalence of a gluten-free diet was higher in females (0.58%) than males (0.37%), although this was not statistically significant (p = 0.34). Participants reporting a gluten-free diet were older (46.6 vs. 40.5 years, p = 0.005), had higher highdensity lipoprotein, lower iron and lower body mass index The estimated national prevalence of non-celiac gluten sensitivity is 0.548%, approximately half that of celiac disease. Future studies are merited in order to better understand the population burden of non-celiac gluten sensitivity Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  91. 91. Non-celiac gluten sensitivity: questions still to be answered despite increasing awareness Cell. Mol. Immunol. 2013 • • • • • • Recently, the increasing number of patients worldwide who are sensitive to dietary gluten without evidence of celiac disease or wheat allergy has contributed to the identification of a new gluten-related syndrome defined as non-celiac gluten sensitivity. Our knowledge regarding this syndrome is still lacking, and many aspects of this syndrome remain unknown. Its pathogenesis is heterogeneous, with a recognized pivotal role for innate immunity; many other factors also contribute, including low-grade intestinal inflammation, increased intestinal barrier function and changes in the intestinal microbiota. Gluten and other wheat proteins, such as amylase trypsin inhibitors, are the primary triggers of this syndrome, but it has also been hypothesized that a diet rich in fermentable monosaccharides and polyols may elicit its functional gastrointestinal symptoms. The epidemiology of this condition is far from established; its prevalence in the general population is highly variable, ranging from 0.63% to 6%. From a clinical point of view, non-celiac gluten sensitivity is characterized by a wide array of gastrointestinal and extraintestinal symptoms that occur shortly after the ingestion of gluten and improve or disappear when gluten is withdrawn from the diet. These symptoms recur when gluten is reintroduced. Because diagnostic biomarkers have not yet been identified, a double-blind placebo-controlled gluten challenge is currently the diagnostic method with the highest accuracy. Future research is needed to generate more knowledge regarding non-celiac gluten sensitivity, a condition that has global acceptance but has only a few certainties and many unresolved issues. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  92. 92. Mucosal cytokine response after short-term gluten challenge in celiac disease and non-celiac gluten sensitivity.Am. J. Gastroenterol. 2013 (5):842-50 • • • • • • • Celiac disease (CD), gluten induces both adaptive and innate immune responses. Non-celiac gluten sensitivity (NCGS) is another form of gluten intolerance where the immune response is less characterized. Comparison of early mucosal immunological events in CD and NCGS by challenging 30 HLA-DQ2(+) NCGS and 15 CD patients, all on a gluten-free diet, with four slices of gluten-containing bread daily for 3 days. Duodenal biopsy specimens were collected before and after challenge. In CD patients, tumor necrosis factor alpha (P=0.02) and interleukin 8 (P=0.002) mRNA increased after in vivo gluten challenge. The interferon gamma (IFN-γ) level of treated CD patients was high both before and after challenge and did not increase significantly (P=0.06). Four IFN-γ-related genes increased significantly. Treated and untreated CD patients had comparable levels of IFN-γ. Increased expression of MxA in treated CD patients after challenge suggested that IFN-α was activated on gluten challenge. In NCGS patients only IFN-γ increased significantly (P=0.03) Importantly, we found that the density of IELs was higher in NCGS patients compared with disease controls, independent of challenge, although lower than the level for treated CD patients.CD patients mounted a concomitant innate and adaptive immune response to gluten challenge. NCGS patients had increased density of intraepithelial CD3(+) T cells before challenge compared with disease Copyrightand 2014 Scot M. controls (c) increased IFN-γ mRNA after challenge. Lewey, DO, FACP, FACG - Peak Gastroenterology
  93. 93. Non-celiac gluten sensitivity: clinical relevance and recommendations for future research. Neurogastroenterol. Motil. 2013 • • • • • • • There has been increasing interest in the entity of Non-Celiac Gluten Sensitivity (NCGS) in recent years; however, it still remains a controversial topic and its pathogenesis is not well understood. Celiac Disease, in contrast, is a well-studied condition that has become increasingly recognized as a prevalent condition arising from a heightened immunological response to gluten Wheat allergy is an IgE-mediated condition capable of causing a variety of gastrointestinal symptoms. However, the number of patients who have neither celiac disease nor wheat allergy, but appear to derive benefit from a gluten-free diet, is also increasing substantially. The use of the term NCGS as a way of describing this condition has become increasingly prevalent in recent years. There is evidence for the condition but it’s putative pathogenesis is in dispute. There are areas of controversy and areas for potential future research. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  94. 94. Is gluten a cause of gastrointestinal symptoms in people without celiac disease? Curr Allergy Asthma Rep 2013 • • • • • The avoidance of wheat- and gluten-containing products is a worldwide phenomenon. While celiac disease is a well-established entity, the evidence base for gluten as a trigger of symptoms in patients without celiac disease (so-called 'nonceliac gluten sensitivity' or NCGS) is limited. The problems lie in the complexity of wheat and the ability of its carbohydrate as well as protein components to trigger gastrointestinal symptoms, the potentially false assumption that response to a gluten-free diet equates to an effect of gluten withdrawal, and diagnostic criteria for coeliac disease. Recent randomized controlled re-challenge trials have suggested that gluten may worsen gastrointestinal symptoms, but failed to confirm patients with selfperceived NCGS have specific gluten sensitivity. Furthermore, mechanisms by which gluten triggers symptoms have yet to be identified but there is recent scientific evidence supporting the entity of NCGS. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  95. 95. Non-Celiac Gluten sensitivity: the new frontier of gluten related disorders. Nutrients 2013 • • • • • • • • Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a "re-discovered" disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA). Although NCGS frequency is still unclear, epidemiological data have been generated that can help establishing the magnitude of the problem. Clinical studies further defined the identity of NCGS and implications in human disease. An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected, requiring even more stringent diagnostic criteria. Several studies suggest a relationship between NCGS and neuropsychiatric disorders, particularly autism and schizophrenia. The first case reports of NCGS in children have been described. Lack of biomarkers is still a major limitation of clinical studies, making it difficult to differentiate NCGS from other gluten related disorders. Recent studies raised the possibility that, beside gluten, wheat amylase-trypsin inhibitors and low-fermentable, poorly-absorbed, short-chain carbohydrates can contribute to symptoms (at least those related to IBS) experienced by NCGS patients. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  96. 96. A UK study assessing the population prevalence of self-reported gluten sensitivity and referral characteristics to secondary care. Eur J Gastroenterol Hepatol 2014 • • • • • • • • • Reports suggest that gluten sensitivity (GS) exists in the absence of coeliac disease (CD). This clinical entity has been termed noncoeliac gluten sensitivity (NCGS). To determine the population prevalence of self-reported GS and referral characteristics to secondary care.A UK population-based questionnaire screened for GS and related symptoms. Diagnostic outcomes were also analyzed in patients referred to secondary care with GS. CD diagnosis entailed a positive coeliac serology (endomysial and/or tissue transglutaminase antibodies) plus Marsh 1-3 on duodenal biopsies. NCGS diagnosis was based on exclusion of CD. Clinical comparisons were made between NCGS and CD.A total of 1002 adults in the population (female 55%, mean age 39 years). The self-reported prevalence for GS was 13% (female 79%, mean age 39.5 years, P<0.0001), with 3.7% consuming a gluten-free diet and 0.8% known to have a doctor diagnosis of CD. Individuals with GS had an increased prevalence of fulfilling the Rome III criteria for irritable bowel syndrome, in comparison with those without GS (20 vs. 3.89%, odds ratio 6.23, P<0.0001). In secondary care 200 GS patients (female 84%, mean age 39.6 years) were investigated, in whom 7% were found to have CD and 93% to have NCGS. All CD patients were human leucocyte antigen DQ2 or DQ8 positive compared with 53% of NCGS cases (P=0.0003). Nutritional deficiencies (P≤0.003), autoimmune disorders (23.1 vs. 9.7%, P=0.0001) and a lower mean BMI (23.7 vs. 25.8, P=0.001) were significantly associated with CD compared with NCGS. GS is commonly self-reported with symptoms suggesting an association with irritable bowel syndrome. The majority of patients have NCGS, an entity which demonstrates clinical and immunologic difference to CD. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  97. 97. Clinical, Serologic, and Histologic Features of Gluten Sensitivity in Children. J. Pediatr. 2013 • • • • • • • Study to describe the clinical, serologic, and histologic characteristics of children with gluten sensitivity (GS). 15 children (10 males and 5 females; mean age, 9.6 ± 3.9 years) with GS who were diagnosed based on a clear-cut relationship between wheat consumption and development of symptoms, after excluding celiac disease (CD) and wheat allergy, along with 15 children with active CD (5 males and 10 females; mean age, 9.1 ± 3.1 years) and 15 controls with a functional gastrointestinal disorder (6 males and 9 females; mean age, 8.6 ± 2.7 years). All children underwent CD panel testing (native antigliadin antibodies IgG and IgA, anti-tissue transglutaminase antibody IgA and IgG, and anti-endomysial antibody IgA), hematologic assessment (hemoglobin, iron, ferritin, aspartate aminotransferase, erythrocyte sedimentation rate), HLA typing, and small intestinal biopsy (on a voluntary basis in the children with GS).Abdominal pain was the most prevalent symptom in the children with GS (80%), followed by chronic diarrhea in (73%), tiredness (33%), bloating (26%), limb pain, vomiting, constipation, headache (20%), and failure to thrive (13%). Native antigliadin antibodies IgG was positive in 66% of the children with GS. No differences in nutritional, biochemical, or inflammatory markers were found between the children with GS and controls. HLA-DQ2 was found in 7 children with GS. Histology revealed normal to mildly inflamed mucosa (Marsh stage 0-1) in the children with GS. Our findings support the existence of GS in children across all ages with clinical, serologic, genetic, and histologic features similar to those of adults. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  98. 98. Seroreactive marker for inflammatory bowel disease and associations with antibodies to dietary proteins in bipolar disorder. Bipolar Disord 2013 • • • • • • • Immune sensitivity to wheat glutens and bovine milk caseins may affect a subset of individuals with bipolar disorder. Digested byproducts of these foods are exorphins that have the potential to impact brain physiology through action at opioid receptors. Inflammation in the gastrointestinal (GI) tract might accelerate exposure of food antigens to systemic circulation and help explain elevated gluten and casein antibody levels in individuals with bipolar disorder. We measured a marker of GI inflammation, anti-Saccharomyces cerevisiae antibodies (ASCA), in non-psychiatric controls (n = 207), in patients with bipolar disorder without a recent onset of psychosis (n = 226), and in patients with bipolar disorder with a recent onset of psychosis (n = 38). We compared ASCA levels to antibodies against gluten, casein, Epstein-Barr virus (EBV), herpes simplex virus 1 (HSV-1), influenza A, influenza B, measles, and Toxoplasma gondii. Elevated ASCA conferred a 3.5-4.4-fold increased odds ratio of disease association (age-, race-, and gendercorrected multinomial logistic regressions, p ≤ 0.00001) that was independent of type of medication received. ASCA correlated with food antibodies in both bipolar disorder groups (R(2) = 0.29-0.59, p ≤ 0.0005), and with measles and T. gondii immunoglobulin G (IgG) in the recent onset psychosis bipolar disorder group (R(2) = 0.310.36, p ≤ 0.004-0.01) Elevated seropositivity of a GI-related marker and its association with antibodies to food-derived proteins and self-reported GI symptoms suggest a GI comorbidity in at least a subgroup of individuals with bipolar disorder. Marker seroreactivity may also represent part of an overall heightened activated immune state inherent to this mood disorder. Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology
  99. 99. Reactivity to dietary gluten: new insights into differential diagnosis among gluten-related gastrointestinal disorders. Pol. Arch. Med. Wewn. 2013 • • • • • The ingestion of dietary gluten sometimes may trigger allergic, autoimmune or nonallergic and nonautoimmune response. The typical gluten-related allergic disorder is the wheat allergy (WA). Celiac disease (CD) is a well-known gluten-related autoimmune condition. The clinical expression of a gluten-related nonallergic and nonautoimmune response is nonceliac gluten sensitivity (NCGS), an emerging condition whose framework is yet unclear and whose diagnosis is suggested only by demonstration of gluten-dependency in patient' symptoms after exclusion of WA and CD. This review discusses the current tools to identify patients suffering from WA, CD, and NCGS, as well as the most recent insights in the differential diagnosis among these gluten-related gastrointestinal disorders . Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  100. 100. Biomarkers of gluten sensitivity in patients with non-affective psychosis: A meta-analysis. Schizophr. Res. 2013 • • • • • • • • • • Dohan first proposed that there may be an association between gluten sensitivity and schizophrenia in the 1950s. Since then, this association has been measured using several different serum biomarkers of gluten sensitivity. At this point, it is unclear which serum biomarkers of gluten sensitivity are elevated in patients with schizophrenia. However, evidence suggests that the immune response in this group is different from the immune response to gluten found in patients with Celiac disease. A systematic literature review was performed to identify all original articles that measured biomarkers of gluten sensitivity in patients with schizophrenia and non-affective psychoses compared to a control group. Three databases were used dating back to 1946 and a meta-analysis was performed of specific biomarkers and reported according to MOOSE guidelines. 17 relevant original articles were identified, and 12 met criteria for the meta-analysis. Five biomarkers of gluten sensitivity were found to be significantly elevated in patients with nonaffective psychoses compared to controls. The pooled odds ratio and 95% confidence intervals were Anti-Gliadin IgG OR=2.31 [1.16, 4.58], Anti-Gliadin IgA OR=2.57 [1.13, 5.82], Anti-TTG2 IgA OR=5.86 [2.88, 11.95], Anti-Gliadin (unspecified isotype) OR=7.68 [2.07, 28.42], and Anti-Wheat OR=2.74 [1.06, 7.08]. Four biomarkers for gluten sensitivity, Anti-EMA IgA, Anti-TTG2 IgG, Anti-DGP IgG, and Anti-Gluten were not found to be associated with schizophrenia. Not all serum biomarkers of gluten sensitivity are elevated in patients with schizophrenia. Copyright in 2014 Scot M. However, the specific immune response to gluten (c)this population differs from that found in patients Lewey, DO, FACP, FACG - Peak with Celiac disease. Gastroenterology
  101. 101. Non-celiac gluten sensitivity. Is it in the gluten or the grain? J Gastrointestin Liver Dis 2013 • • • • • • Celiac disease is an immune-mediated inflammatory disorder of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically predisposed individuals. Over the past several years, the concept of non-celiac gluten sensitivity (NCGS) has gained significant interest from the scientific community and mass media and the number of individuals embracing a gluten-free diet is rapidly growing. This condition is characterized by gastrointestinal or extraintestinal symptoms that respond to gluten withdrawal without evidence for underlying celiac disease or wheat allergy. Symptoms display significant overlap with the irritable bowel syndrome. Many important factors regarding this relatively novel condition remain to be elucidated; no discriminative markers to support a diagnosis of gluten sensitivity have been identified yet and its pathogenesis remains obscure. Here we review the current knowledge on NCGS, and outline potential pathogenic pathways of different gluten related disorders in order to gain clues about the pathophysiology of this(c) 2014 condition. Copyright novel Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  102. 102. • • • • • • • Leonardo da Vinci's face symmetry derives from 3 equal craniofacial segments It has been reported that adult subjects with celiac disease (CD) can be identified on the basis of a greater extension of the forehead in comparison to the medium third of the face. 126 biopsy-proven patients with CD (76 children and 50 adults) and 102 healthy controls (43 children and 59 adults). Their faces were photographed; the pictures were edited using a software program to calculate the facial segments. The tn length was significantly different between adult celiac and adult controls (7.43 ± 1.46 cm vs 6.38 ± 1.73 cm, P = 0.001) 43 of 50 patients (sensitivity 86%), but 34 of 59 controls were positive (specificity 54.2%). The positive predictive value was 56%. Neither the tn length nor the tn/ns ratio in celiacs correlated to the time of gluten exposure. Adults, but not children, with celiac disease show a forehead extension significantly greater than controls, but this test's specificity appears too low to be used in the screening of CD. Leonardo da Vinci meets celiac disease.J. Pediatr. Gastroenterol. Nutr. 2013 (2):206-10Chiara Zanchi, Giovanna Ventura, Grazia Di Leo, Nicoletta Orzes, Luca Ronfani, Tarcisio Not, Alessandro Copyright (c) 2014 Scot M. Lewey, DO, FACP, FACG - Peak Gastroenterology Associates,
  103. 103. • • • • • • • • Food intolerance is a common complaint amongst patients with functional gastrointestinal (GI) disorders (FGIDs), including those with irritable bowel syndrome (IBS), functional dyspepsia, as well as gastroesophageal reflux disease. Although there has been a longstanding interest in the possible role of food allergy in IBS, there are limited data supporting the association. However, the prevalence of food allergy is sufficiently high that patients with FGID may also have food allergies or hypersensitivities. Food intolerances or sensitivities are reactions to foods, which are not due to immunological mechanisms. Lactose intolerance is common in the general population and can mimic symptoms of FGID or coexist with FGID. Other carbohydrate intolerances may be responsible for symptom generation in patients with IBS and perhaps other FGIDs. There is a great interest in the role of a major dietary protein, gluten, in the production of symptoms that are very similar to those of patients with celiac disease without the enteropathy that characterizes celiac disease. Emerging research into a syndrome known as nonceliac gluten sensitivity suggests a heterogeneous condition with some features of celiac disease but often categorized as FGIDs, including IBS.. Dietary proteins and functional gastrointestinal disorders.Am. J. Copyright (c) 2014 Scot M. Gastroenterol. 2013 (5):728-36 DO, FACP, FACG - Peak Lewey, Gastroenterology Associates,
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