The document discusses gluten sensitivity, its related medical conditions (wheat allergy, celiac disease, non-celiac gluten sensitivity), and the complexity involved in diagnosing and treating these conditions. It emphasizes the importance of a systems medicine approach for patients with unexplained symptoms possibly related to gluten, as conventional celiac panels may not provide sufficient information. Additionally, the document highlights the need for awareness of dietary management and potential health risks associated with gluten exposure.

1. Gluten Sensitivity
A Systems Medicine Approach
Keith Berndtson, MD

2. What is gluten?
A. A protein mainly found in wheat, rye, and barley.
B. A chain of peptides including gliadins and glutenins.
C. A substance that gives bread a pleasant texture, and
lends dough more versatility.
D. An additive used to stabilize processed foods.
E. A potentially lethal substance.
F. All of the above.

3. Three Medical Conditions
Related to Gluten Exposure
Wheat Allergy Celiac Disease Gluten Sensitivity
•Allergic •Autoimmune •“GS” cause unknown
•Misc. wheat proteins •Gluten the cause •Innate immune system
•IgE mediated •T-cell mediated •Cytokine mediated
•Histamine release •Leaky gut the trigger •Spectrum of disorders
•Allergy signs •Malabsorption •Malabsorption
•GI, lungs, skin •Multiple tissues •No tissue damage
•Anaphylaxis risk •Many symptoms •Many symptoms
•Hours to minutes •Weeks to years •Hours to days
•Accepted biomarkers •Accepted biomarkers •Proposed biomarkers

4. The Two Types of Gluten Sensitivity
Type 1: Celiac Permissive GS Type 2: Non-Celiac GS
• 3 HLA-DQ genes permit celiac and pre- •No HLA genotype predictors thus far,
celiac disease. research ongoing.
• Celiac panels predict likelihood of celiac •Mechanisms and predictors poorly
disease, not Type 2 non-celiac GS. understood.
• Both malabsorption and leaky gut can •Malabsorption known to occur with this
appear with this form. form but leaky gut may not be required.
• G-free trial helpful to assess non-celiac •G-free trial warranted to help determine
GS even when celiac panel is negative. if symptoms subside off gluten.
•Affects ~1% of population. •Affects ~6% of population.
•3 million Americans have it. •18 million Americans have a form of it.
An estimated 21 million Americans have GS-related health problems.

5. “If you’re suffering with
Doctors are
symptoms that make your
life miserable and you’ve
divided about “It is not a healthy diet
for those who don’t need
investigated all possible non-celiac it. These people are
following a fad,
causes, I don’t see anything
wrong with going on a gluten sensitivity essentially, and that’s my
biased opinion.”
gluten-free diet.”
- New York Times
- Living Without Magazine Feb 4, 2013
Aug/Sep 2011
Alessio Fasano, MD Stefano Guandalini, MD
University of Maryland University of Chicago
Going gluten-free is no walk in the park. While unexplained symptoms
often resolve on a gluten-free diet, the diet can be unhealthy if it leads to
increased junk carb, salt, and fat intake. With leading experts divided...
What is a concerned health consumer to do?

6. When the scientific evidence
is blurry...
seek a
systems medicine approach.

7. vs.
Systems Medicine Reformed Medicine
Says it is patient-centered. Says it is patient-centered.
Feels patient-centered. Feels like a conveyor belt.
Splits cases into unique narratives. Lumps cases into disease groups.
Explanatory power is king. Diagnostic labels suffice.
Listens well. Hard of hearing.
Shared decision-making. Top-down decision-making.
Integrative medicine is valued. To be determined.
Goal: restore functional integrity. Goal: hit productivity targets.
Unhurried curiosity. HMO-like need for speed.
Free to improvise. “Evidence-based” rules dictate.
Accommodates complexity. Downplays complexity.

8. The Wrong Approach
to Diagnosing Gluten Sensitivity
Your medically unexplained symptoms could be gluten-related.
Your doctor orders a celiac panel:
Your Celiac Panel Results
1. anti-transglutaminase IgA = 5 Antibody detected, but not high enough to be called (+).
2. total IgA = 243 The reference range is 81-463 mg/dL, so this is not a low amount of IgA.
3. anti-gliadin (deamidated) IgA = 11 Antibody detected, not high enough to be called (+).
The results are “negative.” You’re told not to worry about gluten.
The advice is incorrect. Here’s why:
1. A celiac panel is not enough to decide if GS is related to your
unexplained symptoms - you need to check your celiac genotype.
2. If your genotype is positive, you could have pre-celiac GS. If it’s
negative, you could nonetheless have non-celiac GS.

9. The Right Approach
to Diagnosing Gluten Sensitivity
Moderate to severe medically unexplained symptoms?
Check the celiac panel and the HLA celiac genotype.
(+) celiac panel (-) celiac panel (-) celiac panel
(+) celiac genotype (+) celiac genotype (-) celiac genotype
>90% have possible possible
celiac disease pre-celiac GS non-celiac GS
Permanently G-free 3-month G-free trial 3-month G-free trial
Better Not better Better Not better
Continue Re-evaluate Continue Re-evaluate
Monitor

10. What is celiac disease?
An autoimmune disease that damages the small intestinal lining.
Marsh 0 Marsh 1 Marsh 2 Marsh 3a Marsh 3b Marsh 3c
The Marsh system for classifying degree of abnormality on biopsy.
From Shag to Berber
Progression from a normal gut lining (0) to total villous atrophy (3b)
can take months to decades for reasons we cannot yet predict.
figure from: Kneepkens, CMF, vonBlomberg BME, Coeliac Disease. European J Pediatrics. 2012 Jul;171(7):1011-1021

11. Gliadin: the Pros and Cons
Gliadin’s Benefits
Cross-linked amino acids make
gliadin a sticky molecule that
holds together as baked dough
rises.
The higher the gliadin content in
the dough, the more chewy the
bread or crust.
Lower gliadin content results in a
flakier bread and crust. No gluten
Sticky free grains contain a perfect
disulfide bridges substitute for gliadin.
Normal digestion breaks protein down into short peptides and single amino acids.
Due to its disulfide bridges, gliadins can resist complete digestion. In people who
are genetically predisposed, undigested gliadin fragments trigger furious immune
responses that can cascade into a surprisingly broad range of health problems.

12. Some of the health problems
associated with celiac disease
Obesity Cerebellar ataxia
Microscopic colitis Neuroimmune disease
Food sensitivities Neuropathy
Iron deficiency Autoimmune arthritis
Magnesium deficiency Autoimmune thyroiditis
Vitamin D deficiency Diabetes
Vitamin B12 deficiency Failure to thrive
Insomnia Infertility
Migraine headaches Osteoporosis
Anxiety Dermatitis herpetiformis
Depression Endometriosis
ADHD Hepatitis
Cognitive dysfunction Recurrent canker sores
Dementia Growth delay

13. Celiac Disease
Leaky Gut Needed to Flip the GS Switch
Diagram source: Fasano A. Surprises from Celiac Disease. Scientific American. 2009 Aug:32-9.

14. Celiac Disease
Suspected Triggers for Leaky Gut
Antibiotics.
Steroids, NSAIDs.
Antacids.
Allergies, toxicities.
GI infections/dysbiosis.
Food sensitivities.
Excess sugar/junk food.
Excess alcohol.
Immunosuppressants. Are you at increased risk for
intestinal hyper-permeability?
Inflammatory disease.

15. Celiac Disease
Ways of Testing for Leaky Gut
Labs that evaluate
intestinal permeability:
Intestinal Lactulose
Permeability: to mannitol
Direct ratio
GI Effects: Comprehensive
Indirect stool analysis
Intestinal
GI-specific
Antigenic
antibody
Permeability:
Indirect
panel
If a leaky gut flipped your GS switch, ongoing gluten exposure could be
ruining your life! Let’s get a celiac genotype check for leaky gut.

16. Celiac Disease
A Commonly Missed Diagnosis
For every 1 person with known celiac
disease, 19 others are undiagnosed.
Ascher H, Kristiansson B. Childhood celiac
disease in Sweden. Lancet, 1994;44:340
Most cases are missed because they
lack typical gastrointestinal symptoms.
Fasano A, Catassi C. Current approaches to
diagnosis and treatment of celiac disease:
an evolving spectrum. Gastroenterology.
2001;120:636.

17. Celiac Disease
Global Prevalence
Kamin DS, Furuta GT. The iceberg cometh: establishing the
prevalence of celiac disease in the United States and Finland.
Gastroenterology. 2003;126(1):359.
In 1980, celiac disease was thought to exist in 1 of 10,000 people. Today the global
prevalence of celiac disease is 1 in 130 - as high as 1 in 30 to 40 in people of Irish or Italian
descent. The prevalence has increased 100-fold because we’re diagnosing more cases, but
also because more cases are occurring as a result of increasing exposure to gluten,
unhealthy lifestyles, and more triggers for leaky gut.

18. Celiac Permissive HLA-DQ Genotypes
DQ2.5 DQ8 DQ2.2
DQA1:05 / DQB1:0201 or 0202 DQA1:03 / DQB1:0302 DQA1:02 / DQB1:0202
1 copy enough, 2 copies high risk. 1 copy enough, 2 copies high risk. 2 copies permissive, one possibly.
A celiac permissive genotype is a necessary but not sufficient condition
for progression to celiac disease.
These HLA-DQ variants are present in more than 25% of the global
population, but only 1% of the population has celiac disease.
The big question is what percentage of people with celiac permissive
genes suffer from pre-celiac disease?
If you have medically unexplained symptoms, you have a higher
pre-test likelihood for celiac, pre-celiac, or non-celiac GS.
If you have unexplained symptoms, the presence of one or more of these
genes always warrants a 3-month G-free trial to rule out pre-celiac disease.

19. HLA Test Reporting Format Matters!
The truth: all labs could do a
Local Hospital Labs better job of HLA DQ reporting.
HLA DQ reports should clearly list detected alpha and beta pairs so
interpreters can tell if a DQ2.2 genotype is present.
Going forward, HLA DQ reports should be viewed as relevant not just
for celiac risk, but also for pre-celiac disease risk.

20. Reasons for Gluten-Free Trial Failures
In one study, a G-free diet for one year proved curative
in 70% of adults diagnosed with CD by biopsy.
What could have gone wrong for the other 30%?
Inadequate nutritional repletion. Might involve protein, iron, B12,
vitamin D, vitamin A, or minerals in various combinations.
Tag-along problems that followed in the wake of CD. These include
weak digestion, other food sensitivities, and gut floral imbalances that
could persist to perpetuate leaky gut and frustrate recovery.
Co-morbid conditions. Separate problems that need to be treated in
their own way for someone to feel better (“the two-thumbtack theory”).
Genetics and lifestyle. Genes load the gun, environment pulls the trigger.

21. CD Natural Histories: Four Cases
Normal Leaky gut pre-celiac celiac
onset
age
7
celiac
dx
age
22 dx
delay:
15
yrs
LG: frequent antibiotics for URIs? PC: nausea, fatigue, growth delay.
Case 1
onset
age
24
celiac
dx
age
45 dx
delay:
21
yrs
LG: frat lifestyle? PC: anxiety, insomnia, joint pains.
Case 2
onset
age
20
celiac
dx
age
59 dx
delay:
39
yrs
LG: steroids? PC: IBD, cerebellar ataxia,
Case 3 migraines. Died
age
70.
onset
age
27
Celiac
dx
by
autopsy.
dx
delay:
43
yrs
LG: parasite? PC: multiple
Case 4 diagnoses, many admissions,
dermatitis herpetiformis.
0 20 40 60 80 100

22. The goal of diagnosis:
Stop missing cases!
Crowd = 100,000 Celiacs = 1,000
Known Celiacs = 50
Pre-Celiacs = ?
Leaky guts = ?
Non-Celiac gluten sensitivity = ?

23. Clearing the Hurdles
So, you’ve been advised
to go gluten free and
you’re thinking...
OMIGOD!
Where do I start?
What have I done?

24. Clearing the Hurdles
With Gluten Gluten-free
light, airy, and springy dense and crumbly
An initial hurdle for many people who’ve been advised to begin a
gluten free lifestyle is finding a satisfying gluten free bread. Such
people routinely clear the hurdle through trial and error and with help
from friends, support groups, and online resources.

25. Some fan favorites

26. Clearing the Hurdles
Certain people with GS also suffer from
tag-along food sensitivities.
These sensitivities commonly include
dairy and sugar, but can include any
GF-grains Meats, nuts number of foods.
fruits, healthy legumes,
carbs dairy To get well, such people may need to
identify and restrict exposure to tag-
along reactive foods.
Vegetables Tag-along reactive food restriction is
almost always temporary (less than 6
months).
Still, some will find that for certain foods,
long-term avoidance works best.
The G-free Plate Method

27. Congratulations!
You’ve learned a systems medicine approach to gluten sensitivity.
Treat yourself to a gluten-free feast!
An app
et
with no izer G-free
bre t:
and G-f ad desser
ree
breadin
g:
refills!
Free
An entree
with
G-free
bread:
to ward off
A cup of Joe a?
ing food com
your impend
Yes, a G-free diet can be unhealthy - but that’s up to you.

28. You can take control of your health!
Now that you know how to solve the gluten puzzle...
and where to find any help you may need along the way.

29. Patient-centered
systems medicine.
15 N. Prospect
Park Ridge, IL 60068
847-232-9800
(for nutrition consults by phone)
www.parkridgemultimed.com