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?
Case Presentation #1
• 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
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
United States Department of Agriculture Economic Research Servicehttps://www.ers.usda.gov/topics/crops/wheat/wheats-role-in-the-us-diet/
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
United States Department of Agriculture Economic Research Servicehttps://www.ers.usda.gov/topics/crops/wheat/wheats-role-in-the-us-diet/
• 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
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/
Wheat's Role in the U.S. Diet Has Changed 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
Adapted from Lauren Van Dam, MS, RD, CNSC
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)
Adapted from Lauren Van Dam, MS, RD, CNSC
Naturally GF Foods
Plain:• Fruits• Vegetables• Nuts/seeds• Legumes• Dairy• Meat/poultry/eggs• Fish/seafood
Adapted from Lauren Van Dam, MS, RD, CNSC
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
Adapted from Lauren Van Dam, MS, RD, CNSC
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)
Adapted from Lauren Van Dam, MS, RD, CNSC
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
No universal symbol exists
Adapted from Lauren Van Dam, MS, RD, CNSC
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
Adapted from Lauren Van Dam, MS, RD, CNSC
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
Case Presentation #2
• 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
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
Non-Celiac Gluten Sensitivity
• Similar to CD– Diarrhea, constipation, bloating, flatulence,
and extraintestinal manifestations– Symptoms may correlated with quantity and
regularity of Gluten consumption
Non-Celiac Gluten Sensitivity
• 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
Non-Celiac Gluten Sensitivity
• 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)
Non-Celiac Gluten Sensitivity
• 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
New therapies on the horizon
– 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
New therapies on the horizon
– 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