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Celiac disease and Wheat IntoleranceGoing against the Grain?

Michael D. Rice, MDMarch 17, 2017

Creating a Space for Wellness: Integrative Health in Primary Care

“We’ve been wrong about what our job is in medicine. We think our job is to ensure health and survival. But really it is larger than that. It

is to enable well-being.”

― Atul Gawande

Outline

• History of Wheat• What is Gluten • Celiac Disease

– Epidemiology– Pathophysiology of CD– Diagnosis and testing– Management details

• NCGS (NCWS)– Rise, increasing prevelance– Impact on more and more of our patients

• Gluten in context of health and wellness

Case Presentation #1

• 35 yo female presents– Bloating, alteration in bowel habits,– Distention and fatigue (2-3 yrs)– Self initiated GFD

• Friend with Celiac Disease– Presents for second opinion

• Feels much better

Your patient has questions...

• Do I have celiac disease?• What is gluten? • Is gluten bad for me?• Should I be gluten free indefinitely?• Why am I not better?


• Do we have confidence in her diagnosis?• What may be causing her symptoms?• What other etiologies for her symptoms

should we consider?• What are the next steps?• How might we counsel her to maintain

health and physical wellness?

What Is Gluten?

• Storage protein – wheat, rye, barley– most oats (cross-contamination)

• Latin for “glue” – gives bread elasticity, helps rise and hold the

shape

• Wheat: comprised of gliadin and gluteninproteins

– Gliadin responsible for immune reaction in celiac dz

• Rich in glutamine and proline residues – Healthy human intestine cannot fully digest

• One of most heavily consumed proteins– for >10,000 years

• World wide wheat utilization – 718.3 million tons

– >200lb/person annually– 8.7 oz per day

Plant Taxonomy

Botany of Wheat seed anatomy

http://people.oregonstate.edu/~calverta/learn/cereal.html

http://people.oregonstate.edu/%7Ecalverta/learn/cereal.html

Spreading of Agriculture and Celiac Disease

• Cereals domestication started 10,000 years ago in the Fertile Crescent…

• Catalhuyuc, the first town in the world was built 9,000 y ago

• Agriculture slowly spread with a East-West gradient (1 Km/y)…

•• CD genes confer disadvantage in

areas of high cereal consumption

INVERSE RELATIONSHIP BETWEEN CD FREQUENCY AND LENGTH OF TIME SINCE THE INTRODUCTION

OF AGRICULTURE ?

Celiac Disease in Iran

• The prevalence of Celiac Disease among 2000 Iranian blood donors is one of the highest in the world (1:166).

• Celiac Disease is a common finding among patients labelled as irritable bowel syndrome (11 %).

• The theory on the East-West increasing gradient of Celiac Disease prevalence does not hold.

Eur J Gastroenterol Hepatol. 2003 May;15(5):475-8.High prevalence of coeliac disease in apparently healthy Iranian blood donors.

Wheat's Role in the U.S. Diet Has Changed Over the Decades

United States Department of Agriculture Economic Research Servicehttps://www.ers.usda.gov/topics/crops/wheat/wheats-role-in-the-us-diet/

• Colonial Era (1600-1700s)– Wheat production was difficult

• New England and much of South

• Wheat flour too $$ for regular use • High transportation costs

– unprofitable• Wealthy principal consumers of

wheat bread• Colonists turned to other crops

(corn)

Flour Costs Begins Falling


Milling costs dropped • Oliver Evans developed

improved milling system - 1790 – Reduced labor needed by half

• Cyrus McCormick’s Reaper -1834 – eliminated manual cutting of

crop • John Deere's steel plow -1837

– accelerated the rate which heavy prairie soils could be tilled

• Reduced production costs and stimulated wheat production

Transportation Costs Begins Falling


• Transportation infrastructure improvements ↓ flour cost – areas wheat not widely grown

• Erie Canal (1817-25)• Railway expansion

– 1/10th cost of hauling grain by road

• New Hard Wheat Flours Support Consumer Demand in Second Half of 19th Century

• Demand for bread stimulated by:• Introduction of hard wheats

– higher protein content– better suited for making bread than soft

• New milling techniques • changed the quality of the flour

Wheat's Role in the U.S. Diet Over the Decades




U.S. consumption of wheat—dropped sharply beginning in 2000(reversing a three-decade)

Wheat consumption 146.3 pounds to a low of 133.4 pounds in the mid-2000sThe drop from 2000 reflected public interest in lowering carbohydrate consumption

Interestingly, the rise in wheat consumption that in the 1970s-1980s also triggered by health concerns. - shifting from animal products to

grain-based foods, including wheat products

- because of concerns about cholesterol and heart disease.

Modern Wheat is Less Nutritious Than Older Varieties of WheatData since the year 1843- measured the amount of nutrients with diff

wheat strains

Mineral content starts declining around 1960- coincides with the introduction of modern

wheat

Evidence that modern introduced around the year 1960 - less nutritious than older varieties of wheat

Today’s wheat has 19-28% less of important minerals - Magnesium, Iron, Zinc and Copper,

compared to the wheat of prior generations

Source: Fan MS, et al. Evidence of decreasing mineral density in wheat grain over the last 160 years. Journal of trace elements in medicine and biology

Increasing Prevalence Over Time

a sea of wheatMedi Belortaja 2010

History of Celiac Disease and Wheat related disorders

• First described -1888 Samuel Gee– “Celiac Affliction”– Bread responsible - following WWII

• Transformed over the years – Overt GI sx → Extraintestinal sx

• Parellel entity NCGS– role of gluten in all cases is not clear– implication of immune involvement by

term “sensitivity” uncertain• Wheat Allergy

– IgE mediated allergy– presence must also be evaluated and

ruled out in selected cases

Gluten & wheat associated disorders

~1%of population

>> 1%of population

< 1%of population

• Positive IgA tTGantibody test

• Abnormal biopsy

Symptoms on gluten exposure

[after allergy and celiac disease excluded]

• History (food diary)

• Skin / RAST

22

Celiac Disease

• Autoimmune disease– Triggered by ingestion of gluten

• Genetically susceptible individuals– DQ2 and/or DQ8 positive HLA haplotype

• Necessary, but not sufficient

• Leading to chronic inflammation of the small bowel mucosa– Intestinal and extraintestinal manifestations

Celiac Disease

A unique autoimmune disorder:– Both the environmental trigger (gluten) and – Autoantigen (tissue Transglutaminase) are known– Elimination leads to a complete resolution of the

disease

CD

Genetics Gluten NECESSARYCAUSES

GenderInfant feeding?InfectionsOthers

RISKFACTORS

Pathogenesis

?

Celiac Disease Pathogenesis

HLA-DQ2 or HLA DQ8

Global Burden of Celiac Disease

North America& Europe

0.6 to 2.5%

SubsaharanAfrica

CD Rare

Finland: ~2.5%

Northern India?3%

SouthEastAsia

CD Rare

Kelly, 2013

Analyzed blood samples from 7800 NHANES (2009-2010). TTG IgA & EMA positiveor reported dx by health care professional on GFD

• CD overall 0.71% (95% CI 0.58 – 0.86%)

• Among whites 1.01% (95% CI 0.78 – 1.31%)

• Hispanics 0.3%• Blacks 0.2%Over 80% were undiagnosed at the time of screening

Rubio-Tapia et al, AJG 2012Murray, Am J Gastroenterol 2015

Celiac Disease:Prevalence in the US

Healthy individuals 1:133First-degree relatives 1:22Second-degree relatives 1:39Symptomatic children 1:25Symptomatic adults 1:68Infertility (idiopathic) 1:16Type 1 diabetes 1:23Autoimmune liver disease 1:12Osteoporosis 1:39

Adapted from Fasano A, et al. Arch Intern Med. 2003;163:286-92; Pietzak M, et al. Gastroenterology. 2002;122(4):A181; Berti I, et al. Gastroenterology. 2000; 118(4).

Celiac Disease:Prevalence in the US (cont’d)

Down syndrome 1:11Short stature 1:25Anemia 1:24Arthritis/joint pain 1:33Fatigue 1:34Asthma 1:35Sjögren’s sydrome 1:49Constipation 1:38

Adapted from Fasano A, et al. Arch Intern Med. 2003;163:286-292.

Increasing Prevalence of Celiac Dz

Murray, Gastroenterology,137 (1) , 2009

Rate of undiagnosed CD in recent cohorts was over 4 fold greater than the airforce cohort ? Due to environmental factors

Increasing Prevalence

• Increased awareness• Increased wheat

consumption • Type of wheat

consumption• Hygiene hypothesis

Gujral et al. World J Gastroenterol. 2012 Nov;18(42)Rubio-Tapia AJG 2012

Present rate of diagnosis in US is 15% (85% of all patients undiagnosed)

Hygiene Hypothesis?

• Our immune system – Developed to constantly fight

germs and parasites• Environment clean and sterile

– Immune system is idle• Modern hygiene leads it to react

against harmless environmental antigens and auto-antigens– our immune systems start to

overreact to things that should be harmless (including foods: wheat or peanuts)

CD

Genetics Gluten NECESSARYCAUSES

GenderInfant feeding?InfectionsOthers

RISKFACTORS

Pathogenesis

?

Celiac Disease Pathogenesis

HLA-DQ2 or HLA DQ8

Genetic Testing

• Human leukocyte antigen (HLA) alleles associated with celiac disease– DQ2 found in 95% of celiac patients– DQ8 found in remaining patients– 30%-40% general population

• Value of genetic testing– High negative predictive value – Negativity for DQ2/DQ8– excludes CD diagnosis with >99%

confidence

Schuppan D. Gastroenterology. 2000;119:234-242.Kaukinen K, et al. Am J Gastroenterol. 2002;97:695-699.

Genetic Factors

• Risk of celiac disease and HLA status:– General population ~ 1%– DQ2 homozygous - 31x– DQ2/DQ8 - 14x– DQ8 homozygous - 10x– DQ2 heterozygous - 10x– DQ8 heterozygous - 2x– DQ2 and DQ8 negative- <0.1x

• High prevalence 1st degree relatives: 10%• Monozygotic twins concordance: 75%-85%

Pietzak,M, Clin Gastro &Hepatol, 7:996,2009Nistico Gut 2006; 55

Environmental Factors

• Breast Feeding – breastfed beyond gluten exposure lower risk?

• Timing of gluten introduction – earlier exposure = higher risk?

• Microbiome?– Cesarean section (increased risk)– GI infections (rotavirus, campylobacter)– Antibiotic use– PPI use

• Iron supplements in pregnancyNOT CLEAR WHY CD CAN OCCUR AT ANY AGE

Celiac Disease “Traditional” Presentation

• Traditionally – Rare malabsorptive

disorder of infancy• diarrhea, edema, wasting

– Rickets, growth failure

Celiac Disease current presentation

• Can present at any age• NOT primarily a GI Dz

– Multisystem disease• Large spectrum in the

clinical presentation

Not all in the Gut

Clinical Presentations- Children

• Diarrhea predominant only 10% of time (very young at dx)

• Occasionally obese at time of dx• Recurrent abdominal pain• Growth problems

– FTT and short stature• Screening in high risks groups

Clinical Presentation- Adult

• Most do not have diarrhea• Most have one of many “non-classic symptoms”

– Anemia (Fe defic or anemia of chronic disease)– Osteoporosis– Abdominal pain– Neurological or psychiatric problems– Infertility– Aphthous stomatitis– Vitamin deficiencies– Dermatitis Herpetiformis

Dermatitis Herpetiformis

• Erythematous macule > urticarial papule > tense vesicles

• Severe pruritus• Symmetric distribution• 90% no GI symptoms• 75% villous atrophy• Gluten sensitive

Garioch JJ, et al. Br J Dermatol. 1994;131:822-826.Fry L. Baillieres Clin Gastroenterol. 1995;9:371-393. Reunala T, et al. Br J Dermatol. 1997;136:315-318.

Celiac Disease Has Many Faces

• Neurological presentations– peripheral neuropathy,

ataxia, epilepsy• Fatigue• Infertility• Autoimmune Disease• Osteoporosis• Dermatitis Herpetiformis• Abnormal LFTs• Anemia• Hypoalbuminemia• Vitamin deficiency

The Celiac IcebergSymptomatic

Celiac Disease

Silent Celiac Disease

Latent Celiac Disease

Genetic susceptibility: - DQ2, DQ8Positive serology

Manifest mucosal lesion

Normal Mucosa

Diagnosis of Celiac Disease

Clinical Suspicion

Positive Serologies

BIOPSY

Serologic Testing for CD

↑ Titer, ↑likelihood of true positiveIgA deficiency (approx 2% of CD)

Total serum IgA vs DGP IgG

BEST COMBO: (Adults) TTG IgA + DGP IgG

(Children <2) TTG IgA + DGP IgA +IgGTTG less sensitive in young children

Antigliadin AbsNo longer recommended

Serologic Test Sensitivity SpecificityTissue transglutaminaseIgA (TTG IgA)

90-98% 95-97%

Endomysial IgA (EMA)

85 - 98 % 97 - 100%

Deamidated GliadinPeptide (DGP) IgA

94% 99%

Deamidated GliadinPeptide (DGP) IgG

92% 100%

Anti-gliadin IgA 75-90% 82-95%

Anti-gliadin IgG 69–85% 73-90%

If clinical suspicion high proceed to biopsy Seronegative CD does exist!

Endoscopic Findings:

Marsh Classification

Pathophysiology of Celiac Disease

• Gliadin is incompletely digested by gastric, duodenal, and pancreatic secretions in humans– leaves toxic epitopes, especially a 33 mer

• Enters lamina propria– Likely during infection

Native Gliadin Peptide

Enterocytes

Antibodiesanti-gliadin

anti-endomysialAnd tissue transglutaminase

Pro-Inflammatory Cytokines

(Interferon-γ, TNF-a, IL-15)

Lymphocytes(T cells , Natural Killer cells and B cells)

Plasma cells

ab T cell receptor

Helper T cell

HLA-DQ2/DQ8molecule

Antigen Presenting Cell

GUT LUMEN

LAMINA PROPRIA AND INTRA EPITHILIAL SPACE

33 mer

tTG

Villi flattening ↑IELs Crypt elongation

Inflammation & Damaged Enteroctytes

Green PH, et al. Lancet. 2003

Initial Diagnosis: Management

• Strict GFD -> refer to dietician– Additional lab work :

• CBC, iron studies, folic acid, vitamin B12, vitamin D, calcium, zinc, copper, LFTs (alk phos can be marker of bone disease), PTH level (may be a useful prognostic factor for bone disease)

• DEXA scan• If abnormal refer to endocrine for treatment and repeat in 3-5 years• If normal repeat in females at menopause, males at age 55

• Vaccinate: Pneumococcal vaccine and flu vaccine – HiB (children) and meningococcus vaccine given hyposplenism

• Calcium intake 1000mg/day, supplement Vit D if ↓levels• Advise screening of 1st degree relatives• Celiac Support Group

• https://simplygluten-free.com/celiac-support-groups-community

Rubio-Tapia Am J Gastroenterol 105 (6):1412, 2010

Gluten Free Diet

• Symptoms improve in a few weeks, and ~2/3rds have complete resolution within 6 mos– Antibody levels fall soon after starting GFD

• but may take longer to completely normalize• After 6-12 months on GFD, 80% will have neg serology

– Histology can take years to normalize • some never recover completely

Rashtak, et al. Clin Gastroenterol Hepatol 2008

Follow up

• First follow up in 3-6 months, then yearly if doing well– Assess symptoms, serology

• (TTG IgA and labs abnormal prior testing: Fe, LFTs)– If inadequate response→refer back to dietician

• (sx not improving, Ab titers not decreasing, etc) • If good adherence to GFD, eval for other causes of

non-responsive CD – Consider repeat bx to assess mucosal healing at

2 yrs

Adapted from Lauren Van Dam, MS, RD, CNSC

Obvious Sources of Gluten

• Bread • Cakes• Cereal/granola bars • Cookies • Crackers• Pasta• Pita bread• Pizza• Fried/breaded foods


Less Obvious Sources• Baking powder (wheat)• Beer, brewer’s yeast (wheat,

barley)• Broth and soups (barley, wheat)• Brown rice syrup (barley)• Candy, chocolate (wheat,

barley)• Communion wafers (wheat)• Deli meat, meatballs, sausage

(wheat)• Flavored vinegars (barley)• Imitation seafood (wheat)• Malted beverages (barley)• Marinades, dressings,

seasoning packets (wheat, barley)

• Miso (wheat, barley, or rye)• Natural/smoke flavors

(barley—rare)• Playdoh (wheat)• Rice pilaf (wheat)• Sauces, gravy (wheat)• Soy sauce, teriyaki (wheat)• Seitan (vital wheat gluten)• Stuffing (wheat)• Tea (barley)• Vitamins, supplements,

medications (wheat, barley, oats)


Naturally GF Foods

Plain:• Fruits• Vegetables• Nuts/seeds• Legumes• Dairy• Meat/poultry/eggs• Fish/seafood


Naturally GF Grains/Starches• Almond meal• Amaranth• Arrowroot• Buckwheat • Cassava bean flour• Chickpea flour• Corn/corn flour• Flax• Gums: xanthan,

guar, acacia

• Millet• Potato/potato starch• Quinoa/Quinoa flour • Rice- all varieties• Soy flour• Sorghum • Tapioca starch/flour• Teff


GF Diet Basics

• Fresh Whole Foods: – fruit, vegetables, plain meat, eggs, and dairy – no label reading required/low risk for

contamination • Purchase packaged foods

– Labeled gluten-free →risk of cross-contamination• Label reading for gluten-containing ingredients

is a must for packaged food• Always buy GF certified flours and grain

products (rice flour, corn chips, cereal, rice pasta, etc)


FDA GF Labeling LawFDA rule as of August 5, 2014• Products w/the words “Gluten-Free,” “No gluten,” “Free

of gluten,” “without gluten” must have <20ppm gluten in end product

• Covers cross-contamination but does not require testing • Covers most packaged foods, vitamins/supplements• Voluntary for manufacturers to label foods gluten-free• Does not cover USDA foods (meat, poultry, and

processed egg products), alcohol, or medicine – USDA is working towards adopting the same standards

(currently 80-90% compliance)– www.glutenfreedrugs.com

Thompson T. The Gluten-Free Labeling Rule: What Registered Dietitian Nutritionists Need to Know to Help Clients with Gluten-Related Disorders. Journal of the Academy of Nutrition and Dietetics, 2015 Vol. 115, Issue 1, 13 - 16

http://www.glutenfreedrugs.com/

No universal symbol exists


Gluten-Free Product Certification

• Gluten Intolerance Group (GIG) Gluten-Free Certification Organization (GFCO)– Products contain <10 ppm gluten– Most common symbol

• Celiac Support Association (CSA)– Products contain <5ppm

• Beyond Celiac– Formerly named National Foundation

for Celiac Awareness/Quality Assurance International (NFCA/QAI)

– Products contain <10ppm


What about our patient?

• 35 yo female presents– Bloating, alteration in bowel habits,– Distention and fatigue (2-3 yrs)– Self initiated GFD

• Has friend with Celiac Disease– Presents for second opinion

• Improvement, but ongoing GI sx– diarrhea, bloating, abdominal cramping

ACG Guidelines:

“CD should be differentiated from non-celiac gluten sensitivity in order to identify

risk for nutritional deficiency states, complications of CD, risk for CD and

associated disorders in family members and to influence the degree and duration of

adherence to the GFD.”

Screening for Celiac Disease• Important because:

– Unlike CD, NCWS is not associated with intestinal damage, short stature (children), infertility, nutrient deficiencies, lymphomas, osteoporosis, or increased risk for other autoimmune conditions

– Health risks → strict lifelong diet adherence– Proper diet education on GFD– Medical follow-up (serology testing, etc)– Work, school accommodations– Tax deductions for cost of GF foods

What if patient already on GFD before diagnosis?

• Test for HLA-DQ2/DQ8 to try to exclude CD prior to embarking on formal gluten challenge

• Gluten challenge: – 3 grams gluten daily for 4 weeks

• (typical slice wheat bread=5g)

– then perform EGD with bx and TTG IgA/DGP IgG– If pt having a difficult time with gluten challenge

• consider bx/antibody testing after 2 wks

Rubio-Tapia Am J Gastroenterol 105 (6):1412, 2010

Gluten challenge: making it easier

Improvements:1. Genetic test before

challenge – if negative no challenge

2. Lower dose of gluten (3g versus 10-15g)

3. Option for 2 week dropout (>90% accuracy)

4. Late blood work to increase sensitivity further

1.

3.2.

4.

2013 American College of Gastroenterology Guidelines for Gluten Challenge in Celiac disease 66

Persistent Symptoms

95% of patients with CD improve on GFD

• Wrong diagnosis– Positive Abs on gluten containing diet– Review initial pathology, with GI pathologist– ?HLA DQ2/8 testing

• Ongoing gluten ingestion – Intentional or unintentional

Leffler , CGH, 5:445, 2007


• 36 yo female diagnosed with celiac disease 2 years ago – (friend of patient #1)

• Seeks second opinion of ongoing GI sx (diarrhea, bloating, abdominal cramping) despite reported compliance with GFD for 1 year

• If dx is correct - By definition she has non-responsive celiac disease

• NRCD–No response despite 6 months on GFD

–Recurrence of celiac-related features despite GFD compliance

What is Non-Responsive CD?

Rubio-Tapia, Am J Gastroenterol 108 (5) 2013Leffler , CGH, 5:445, 2007

– Ongoing gluten exposure 36%– IBS 22%– Refractory CD 10%– Lactose deficiency 8%– SIBO 6%– Microscopic colitis 6%– Miscellaneous 13% (PUD, CVID, gastroparesis, Crohn’s, eating disorders, malignancy)

Most common etiologies of Non-Responsive CD

Leffler , CGH, 5:445, 2007

Compliant with GFD? Refer to dietician +TTG IgA titers can support ongoing gluten

exposure (neg abs do not exclude intermittent or low-level gluten

ingestion sufficient to cause symptoms)

EGD with biopsy

Initial evaluation for NRCD

Persistent symptoms

EGD with biopsy

VA

* Special path studies for RCD* SIBO testing* Quantitative Igs* Anti-enterocyte Abs* Giardia testing* H.Pylori testing* ?Tropical sprue (Abx tx)* Evaluate for Crohn’s disease

No VA

*Breath testing for carbohydrate malabsorption

*Colonoscopy – eval for microscopic colitis

*Fecal elastase for pancreatic insufficiency

*IBS - eval and treat

• Villous atrophy • Persistent/recurrent malabsorptive sx

– despite adherence to strict GFD ≥12 months and– other etiologies excluded

• Rare- 1-2% of CD patients• Primary form- no initial response to GFD• Secondary- loss of response to GFD• TTG often normal

• but positive serologies can be present in up to 30% of patients despite good compliance with GFD assessed by dietician interview

Refractory celiac disease

Rubio-Tapia & Murray Gut, 59:547; 2010

TCR αβ

Refractory Celiac Disease

• Type I: (85%) phenotypically Normal IELs

– CD3+ and CD8+– Polyclonal TCR– Pathogenesis: self-perpetuated

inflammation cause by autoimmunity– Good prognosis (93% 5 year survival)

• Type II: (15%) Abnormal IELs– loss of the normal surface markers

CD3, CD4, and CD8 -– preserved expression of

intracytoplasmic CD3 in >50% of IELs and TCR clonal rearrangement

– Resembles low-grade lymphoma– Poor prognosis

Cellier et al. Gastroenterology 1998 (114)Cellier et al. Lancet 2000 (356)

CD8

CD3

CD3

• Prognosis poor in type II– RCD II has 5 year survival 44-58%

• (compared with 93% type I) – High risk of lymphoma

• EATL associated with RCDII – occurs in 60-80% of patients within 5 years

• 5 year survival <20%

Refractory celiac disease

Malamut Gastroenterology 136:81, 2009Rubio-Tapia & Murray Gut, 59:547; 2010

Mortality in celiac disease

• Mortality rate in CD exceeds general pop by 1.24-3.8x– mainly due to malignant disease and malabsorption

• Reduction in excess mortality after 1–5 years on GFD

• Suggesting diet is protective against malignant disease

1Tio et al, APT 2012 35 (5)2Logan RF et al, Gastroenterology 1989; 97: 265–713 Cottone M et al Dig Dis Sci 1999; 44: 2538–41.4 Corrao G et al Lancet 2001; 358: 356–61.5 Holmes et al Gut 1989;30

Back to our patient

• TTG IgA <20• Dietician eval found her to be

compliant with GFD• Duodenal biopsy with no

ongoing VA• Breath testing positive for

lactose intolerance• Symptoms improved with

lactose avoidance and treatment of IBS

Why Gluten Free?

• 38% who choose GF foods – “improved health”

• People w/o CD drive greatest market growth– 82% choose GF for reasons other than CD– Weight loss*

– Reduction in symptoms of IBS, IBD• Important nutritional considerations to

examine when following such a plan

Topper A. http://www.mintel.com/blog/food-market-news/gluten-free-consump tion-trends. Published November 21, 2014

http://www.mintel.com/blog/food-market-news/gluten-free-consump

Nutrient Gaps on GFD

• If not properly planned →potential nutrient gaps• Screen for nutritional deficiencies at time of dx• Common deficiencies

– iron, B vitamins, magnesium, calcium,– fat-soluble vitamins (A, D, E, and K)

• Wheat is commonly enriched with B vitamins– Thiamin, riboflavin, niacin and folic acid

• Gluten free versions bread, pasta, cereal and cracker– Generally Not fortified

Downside of Gluten Free Diet?

GFD may be associated with Increased Blood Levels Of Arsenic And Mercury

• Population-based cross-sectional NHANES study 2009-2012• N=11,353 participants (55 dx’d celiac disease) • collected data on levels of lead, mercury, arsenic and cadmium • subjects who were on a GFD (n=115) and not on a GFD (n=11,235)

• ↑ in heavy-metal bioaccumulation among GFD – below toxic thresholds (except urinary arsenic levels)

• GFD is not medically imperative should be made aware of the possibility of heavy-metal

• bioaccumulation associated with a GFD. • Studies are needed to determine the long-term effects of accumulation of

these elements in persons on a GFD.

Accumulation of Heavy Metals in People on a Gluten-Free Diet Raehsler, Choung, Murray, Clinical Gastroenterology and Hepatology (2017)

Wheat Allergy Celiac Disease*

NC Gluten Sensitivity

Mechanism IgE-mediated Autoimmune ?

Prevalence <1% (children) ~1% ?

Symptoms Hives, congestion, nausea,anaphylaxis

Bloating, diarrhea, weight loss

GI and non-GI

Diagnosis HistorySkin / RAST

TTGBiopsy

Sx w/ Gluten [WA and CD excluded]

Triggers Wheat Gluten Gluten+Treatment Avoid Wheat Gluten free diet Avoid gluten+

Spectrum of Gluten-Related Disorders

*other autoimmune-mediated disorders: gluten ataxia, dermatitis herpetiformis

Non-Celiac Gluten Sensitivity

Three consensus conferences since 2010– Lack of diagnostic biomarkers and uncertainty about clinical

entity– All 3 reports concluded NCGS be defined by following

exclusionary criteria:

1. Clinical entity induced by ingestion of gluten leading to intestinal and/or extraintestinal symptoms

2. Sx resolve once the gluten containing foodstuff is eliminated from diet

3. Celiac disease and wheat allergy have been ruled out

Clinical Presentation NCGS

• Sx occur within hours to days after ingestion• Sx disappear when these grains eliminated• Intestinal symptoms

– IBS-like abd pain, gas distension , irregular BMs• Extraintestinal sx

– HA, foggy mind, chronic fatigue, depression– joint and muscle pain, eczema


• Similar to CD– Diarrhea, constipation, bloating, flatulence,

and extraintestinal manifestations– Symptoms may correlated with quantity and

regularity of Gluten consumption


• Differs from CD– No available biomarkers to confirm Dx– No antibodies– No damage to small intestinal mucosa on bx– No nutrient malabsorption– Cross-contamination of foods with small

amounts of gluten is NOT a concern


• Potential confounder is possible sensitivity/intolerance to other food components

• Feel better with “gluten” removal – larger array of foods may be responsible

• Highly fermentable carbohydrates: FODMAPs– Fructans category includes:

• gluten-containing grains (wheat, rye, barley), onions garlic and chicory root

IBS and NCGS

• 34 IBS patients without constipation (CD ruled out)

• Self-reported gluten sensitivity • GFD symptoms controlled gluten

(n=19) or placebo (n=15)• 16g gluten/day induced rapid onset of GI

symptoms and tiredness within 1 week (6 week long intervention) compared to placebo group

Biesiekierski et al, Am J Gastroenterol 2011

Gluten vs. FODMAPs

• Randomized, double-blinded, placebo-controlled, dose-finding, crossover design

• Significant improvement in GI symptoms and tiredness during a low FODMAP diet

• No change in symptoms with low or high gluten challenges

Biesiekierski et al, Gastroenterology 2013

Food Intolerance

FODMAPs

NCWS Diagnostic Algorithm

Kabbani et. al Am J Gastro, 2014

NCGS Pathogenesis

• Gluten is cause of celiac dz– Not as clear with NCGS

• Other components that induce sxincluding:– FODMAPs– Amylase Trypsin Inhibitors (ATIs)


• Controversial and debated discussions role of gluten in causing NCGS

• Recent studies have indicated – Gluten might NOT be the cause of NCGS

• “Non-Celiac Wheat Sensitivity”

Wheat ATIs

• Amylase-Trypsin Inhibitors• “Natural Pesticide”

– Plant-derived proteins that inhibit enzymes of common parasites in wheat

• Mealworms, meal bugs• Thought to be involved in Baker’s Asthma• May be recognized as foreign

– Triggering an immune response in intestine• In celiac and non-celiac patients

• Role in NCWS not fully defined

Y. Junker et al

Wheat ATIs

• In vitro and in vivo studies suggest– Induce innate immune responses– Involve monocytes, macrophages and dendritic

cell activation of TLR4 complex• Feeding ATIs to mice

– Increase intestinal and systemic release of cytokines and chemokines (IL-18, TNF-a)

• within 2-12 hours• Study of biopsy specimens in CD pts

– Show ATIs ↑ the gluten specific T-cell response

Future Directions

• Over past decades wheat gained popularity– Alterations increase production, pest resistance,

baking properties– Increased speed of wheat-flour processing,

eliminating fermentation before baking– Changes altered macronutrient profile

• protein and immunogenic peptides

• These changes might have contributed to increased prevalence of celiac disease and potentially NCGS in past few decades

New therapies on the horizon

• Why do we need therapies other than GFD?– Suboptimal results with GFD:

• Difficult to avoid gluten exposure/adhere to diet– Study from England n=287

» 40% reported intentional gluten exposure» only 29% reported that they had not been exposed to

any gluten either intentionally or inadvertently

• Ongoing small intestinal injury – despite best efforts to comply with diet

Rubio-Tapia Am J Gastroenterology 2010Hall et al, Appetite, 2013.

† VAS: 0 = Very Easy100 = Very Difficult

020

4060

8010

0

CD GERDHTN DMESRD CHF IBD IBS

Perceived Treatment Burden

44.9

23.5* 21.3*

56.4

41.7 38.4

31.9

40.4

*Compared with CD, p<0.001

Renal disease on Hemodialysis = 56.4

Celiac disease = 44.9

Higher than:• Insulin dependent diabetes• Irritable bowel syndrome• Congestive heart failure• Inflammatory bowel disease• Hypertension• GERD

Perceived treatment burden of GFD is very high

VAS

†

BIDMC Celiac Center 2013 – under review 100


– A few agents studied in Phase I / II clinical trials– Most agents

• intended to serve as an adjunct to the GFD and• mitigate effects of low doses of gluten ingestion

– Therapies involving the development of immune tolerance

• have potential to allow resumption of gluten-containing diet

Leffler, Gastroenterology 148:1311, 2015


– Larazotide Acetate• tight junction regulator

– ALV003• endopeptidase that degrades immunogenic peptides in the

lumen that are resistant to human enzymes– BL-7010

• polymer that binds to gliadin in the lumen– Nexvax 2

• gluten vaccination– Hookworm

• promotes immune regulation with tolerance to gluten

Leffler, Gastroenterology 148:1311, 2015

Modern wheat

• Evidence that modern wheat – harmful to people with gluten

sensitivity, compared to the older varieties

• Einkorn is the oldest and most primitive cultivated wheat

• Study compared the effects of Einkorn (old) and modern wheat on intestinal cells from celiac patients

• Compared to modern wheat, Einkorn didn’t demonstrate harmful effects

Lack of intestinal mucosal toxicity of Triticum monococcum in celiac disease patients.Pizzuti D1, Buda A, D'Odorico A, D'Incà R, Chiarelli S, Curioni A, Martines D.

Microbiota

Microbiome and Gluten Ann Nutr Metab 2015;67(suppl 2):28–41Sanz et al. Nutr Hosp 2013;28: 464–73Br J Nutr 2014;112:30–40

Development of microbiome-informed strategies • personalized preventive and therapeutic measures for

immune-mediated disorders Dietary strategies • optimize partnership between gut microbiota and host

immunity• increasing its stability and resilience to disease

Identification host pathways modulated by the microbiota and their agonists could provide feasible approaches to improve dzmanagement

Small double-blind, randomized, placebo-controlled trial in which they assessed an exploratory intervention in children newly diagnosed with CD)• In comparison to placebo• GFD daily Bifidobacterium longum CECT 7347 • ↓ levels of potentially pro-inflammatory Bacteroidetes fragilis

bacteria, secretory IgA, activated T-lymphocytes, and tumor necrosis factor-X

• might “contribute to the recovery of immune homeostasis in CD”

“Let food be thy medicine and medicine be thy food”

~Hippocrates

Further evaluation needed

Stimulate healthy intestinal flora and intestinal repair

• Licorice root• Apple pectin - remove unwanted toxins and heavy metals • Marshmallow root controls and soothes intestinal inflammation• Aloe vera extract - promote intestinal repair• Paprika • Dandelion• Garlic• Grapefood seed extract• Chamomile• Wormwood

Take-away Points

• Celiac disease is common and increasing in prevalence – remains significantly underdiagnosed, especially in the developing world

• GFD is the mainstay of treatment– GFD not necessarily a Healthy Diet

• Ongoing ingestion of gluten is the major cause of persistent sx• NCWS is an emerging clinical entity

– likely a heterogeneous group overlapping with IBS and celiac disease

• More research is needed – establish risk factors, biomarkers, definitive diagnostic criteria – before patients will truly be able to reap the rewards

• Multiple potential new therapies are being studied – may lead to paradigm shifts in how we manage CD and wheat intolerance

“We look for medicine to be an orderly field of knowledge and procedure. But it is not. It is an imperfect science, an enterprise of constantly

changing knowledge, uncertain information, fallible individuals, and at the same time lives on the line…The gap between what we know and what we aim for persists. And this gap complicates everything

we do.”

― Atul Gawande

U of M Celiac Disease Program• http://www.uofmhealth.org/conditions-

treatments/digestive-and-liver-health/celiac-disease• Celiac Protocol

Chey Eswaren Kao Rice Saad Lee

http://www.uofmhealth.org/conditions-treatments/digestive-and-liver-health/celiac-disease

Documents

Creating a Space for Wellness: Integrative Health in ... · Creating a Space for Wellness: Integrative Health in Primary Care ... – Rise, increasing prevelance – Impact on more