Celiac Disease & Non Celiac Gluten SensitivityChanda K. Ho, MD MPH

March 23, 2013

Objectives Gluten Free Diet Diagnosis and Management of Celiac

Disease Irritable Bowel Syndrome and Celiac

Disease Non-Celiac Gluten Sensitivity Recommendations

Wheat (Triticum spp) 1st cultivated approximately 10,000 years

ago in fertile crescent Relatively novel to man’s diet 2010 world production 651 million tons

3rd most-produced cereal after maize (844 million tons) & rice (672 million tons)

Major diet component b/c need to increase agricultural production

Wheat, Barley, Rye

Wheat Gluten- main structural

protein complex Primary proteins are

gliadin and glutenin. Gliadin contains bulk of

toxic complements- contains repeating patterns of AA that GI tract cannot break down

Gluten “The New Diet Villain” High profile celebrities New Diet Fad Public has adopted this

concept quite readily Google: PubMed

searches- 4,598: 1

Springen K. Newsweek. 2 Dec 2008

www.nytimes.com

Gluten Free Diet

15-30 million Americans are buying gluten free products

$2 billion of gluten free products sold in 1 year

Public awareness of non celiac gluten sensitivity in US has been shown to be higher than that of celiac disease

Di Sabatino et al. Ann Intern Med 2012

Gluten-Free Diet Foods containing wheat, rye, and barley OK to eat: soybean/tapioca flours, rice, corn,

buckwheat, potatoes Read labels on prepared foods/condiments, may

contain stabilizers/emulsifies that have gluten Wine is gluten free. Avoid beers, ales, lagers,

and malt vinegars. Dairy may be not well tolerated given secondary

lactose intolerance Limit oat consumption

Diagnosing Celiac Disease

Celiac Disease (CD): definition

Chronic immune-mediated disease in genetically susceptible individuals

Environmental precipitant- gliadin (toxic fraction of gluten protein)Found in wheat, rye, barley

Improvement with gluten withdrawal Clinical manifestations are variable

Classical CD

Symptoms of malabsorption such as steatorrhea, weight loss, or other signs of nutrient or vitamin deficiency [12].

The presence of characteristic histologic changes (including villous atrophy) on small intestinal biopsy.

Resolution of the mucosal lesions and symptoms upon withdrawal of gluten-containing foods, usually within a few weeks to months.

The Celiac Iceberg

SymptomaticCeliac Disease

Silent Celiac Disease

Latent Celiac Disease

Genetic susceptibility: - DQ2, DQ8 Positive serology

Manifest mucosal lesion

Normal Mucosa

Potential

Asymptomatic/

Non-classical CD

Definitions of Celiac Disease CLASSIC: malabsoprtion, fully developed villous

atrophy, GI symptoms ATYPICAL: no GI symptoms but evaluated for

IDA, anemia, short stature, osteoporosis, etc SILENT: no symptoms, no

features/complications, found incidentally LATENT: CD pts who responded to have a GRD

and have normal histology OR pts with normal histology now on GFD who go on to develop CD (normal mucosa, +Ab test)

AGA Technical Review, Gastro, 2006.

Who Should Be Tested?

GI symptoms including chronic/recurrent diarrhea, malabsoption, distension, bloating

Symptoms suggestive of IBS and/or Lactose Intolerance

Patients with Type 1 DM, Autoimmune disorders, 1st/2nd degree relatives of individuals with CD, Down, Turner, or Williams syndromes

Who Should Be Tested? Iron Deficiency Anemia Folate/B12 deficiency Persistent elevation in AST/ALT Short Stature Delayed puberty Recurrent migraines Recurrent fetal loss Low Birthweight Infants

Serologic TestingSerologic Test

Sensitivity %

Specificity %

Features

IgA AGA 85-90 90 ELISAFalse positive with mucosal damageReplaced by other markers

IgA EMA 97.4 99.6 Immunofluorescence with human umbilical cord or monkey esophagusSubjective, time consuming, expensive

IgA TTG 95.1 98.3 ELISA, human recombinant or RBC-derivedNonsubjective, less expensiveLoss of specificity with autoimmunity

IgA DGP 95 97 ELISAPositive in 80% of cases w/ IgA defDeamidated gliadin peptides

Rostom et al. Gastroenterol 2006

Guidelines for Diagnosis of Celiac Disease Typical symptoms of CD Positivity of serum CD IgA class autoantibodies

at high titer HLA-DQ2 and/or HLA DQ8 genotypes Celiac enteropathy found on small bowel biopsy

Crypt hyperplasiaVillous atrophy Intraepithelial lymphocytosis

Response to a GFDESPGHAN Guidelines for Diabnosis of

Celiac Disease

Monitoring Response to GFD 70% with noticeable clinical improvement within 2

weeks. Symptoms > Histology Patients should be evaluated 4-6 weeks after

starting GFD Use of serologic testing to monitor response

Normal levels do not necessarily mean histologic recovery Levels which do not fall, however, indicate ongoing gluten

ingestion (intentional or inadvertent) Requires pre-treatment elevated levels to be clinically useful

Genetic Testing for Celiac Sprue

Human leukocyte antigen (HLA) alleles associated with celiac disease

Sensitive but NOT specific 30% Caucasians carry DQ2 or DQ8 A negative test excludes celiac disease

with 99% confidence

Schuppan D. Gastroenterology. 2000: 119: 234-242

Kaukinen, K, e al. Am J Gastroenterol. 2002: 97: 695-699

?Repeating Small Bowel Biopsies If nonresponder to GFD Confirm mucosal healing

Nonresponders Patients with poor compliance or

inadvertent ingestion of gluten May have histologic features that overlap

with CD but due to another undiagnosed disorder

Concurrent IBS, lactose intolerance, SIBO, pancreatic insufficiency, microscopic colitis

Refractory sprue Ulcerative jejunitis or intestinal lymphoma

Other factors to consider in CD management Nutritional Deficiencies: iron, folic acid,

calcium, Vit D Constipation (GFD are low in fiber)- Rx

with psyllium Prevention of bone loss evaluate with

DEXA scan Pneumovax Dermatitis herpetiformis

IBS and Celiac

Rome III Criteria for IBS

Recurrent abdominal pain or discomfort, at least 3 days/month in the last 3 months associated with 2 or more of the following Improvement with defecationOnset associated with a change in frequency

of stoolOnset associated with a change in form of

stool

Longstreth et al, Gastroenterology 2006: 130: 1480-1491.

IBS and diet Individuals with IBS complain of subjective food

intolerance twice as much as controls Up to 25% of general US pop believe they have

a food allergy True FA 4-8% children, 1-4% adults 50-90% presumed food allergies are food intolerance

or aversion (non-immune mediated)

Eswaran et al Gastro Clin N Am 2011

IBS and Celiac Disease

Event IBS patients % Gen Pop %

Colitis/IBD 0.51-0.98 0.3-1.2

CRC 0-0.51 0-6 (age dep)

Thyroid dysfxn 4.2 5-9

Celiac sprue 3.6 0.7

Lactose intol 38 26

Cash et al. Am J Gastroenterol 2002; 97:2812.

Date of download: 8/6/2012Copyright © 2012 American Medical Association.

All rights reserved.

From: Yield of Diagnostic Tests for Celiac Disease in Individuals With Symptoms Suggestive of Irritable Bowel Syndrome:  Systematic Review and Meta-analysis

Arch Intern Med. 2009;169(7):651-658. doi:10.1001/archinternmed.2009.22

Screening for Celiac Disease

Routine serologic screening for celiac sprue should be pursued in patients with diarrhea predominant IBS and mixed IBS (Grade 1B recommendation)

ACG Functional Bowel Disorders Task Force 2009

What is Non-Celiac Gluten Sensitivity?

Definitions

Encompasses a collection of medical conditions where gluten has an adverse effect

Can be clinically indistinguishable from celiac sprue but testing often negative or inconclusive

Improves with a gluten free diet

Murray et al. Am J Gastroenterol 2009

Gluten Sensitivity

Celiac DiseaseIBS

Verdu EF, et al. Am J Gastroenterol 2009: 104: 1587-94.

Non-Celiac Gluten Sensitivity

Cases of gluten reactions in which neither allergic nor autoimmune mechanisms can be identified.

Diagnosis by exclusion Prevalence of extraintestinal symptoms

such as behavioral changes, bone or joint pain, muscle cramps, leg numbness, weight loss and chronic fatigue

Non-Celiac Gluten Sensitivity Still not a well-defined clinical entity There are data to suggest improvement in

symptoms on a GFD in non-celiac patients

Di Sabatino, J Clin Gastoenterol 2013

Non-Celiac Gluten Sensitivity Abdominal pain 68% Eczema/rash 40% Headache 35% Foggy mind 34% Fatigue 33% Diarrhea 33% Depression 22% Joint pain 11%

Non-Celiac Gluten Sensitivity

Only recently has this been formerly studied

Strongest evidence of this entity- DBRC trial of FODMAP-depleted gluten in 34 patients who had celiac dz excluded..

Gibson et al. Am J Gastroenterol 2012: 657-665

Effect of Gluten on Symptoms in IBS Patients

Biesiekierski et al Am J Gastroenterol 2011;10:1038

Effect of Gluten on Pain/Bloating in IBS patients

Biesiekierski et al Am J Gastroenterol 2011;10:1038

Effect of Gluten on Fatigue on IBS patients

Biesiekierski et al Am J Gastroenterol 2011;10:1038

Proposed Management for Patients with IBS-like symptoms and minimal histologySymptom LD HLA Serology Treatment

IBS + + + GFD

IBS + Consider other cause

IBS - + + Consider GFD

IBS - - - Tx IBS

Eswaran et al Gastro Clin N Am 2011

Verdu Am J Gastro 2009

FODMAP diet in the management of Functional GI symptoms Fermentable Oligo-di and Mono

Saccharides and Polyols Induce luminal distension, food chemicals

that stimulate the Enteric Nervous System and gluten may trigger symptoms in non-celiacs via an unknown mechanism

Fermentable readily by bacteria, slowly or poorly absorbed by small intestine

FODMAPS

Fruits with fructose > glucose Fructan containing vegetables Wheat based products Sorbitol and lactose containing foods Raffinose containing foods Increasingly being recommended to

manage patients with functional GI symptoms

Remaining questions

Is this just potential celiac disease? Do patients without evidence of celiac

disease who are interested in GFD need to be on a strictly GFD or just decrease gluten?

Are other components of wheat causing symptoms?

Nocebo effect?

Conclusions Non-celiac gluten sensitivity currently

encompasses a broad array of disorders ranging from potential CD to food hypersensitivity to IBS with identified food trigger.

Several proposed mechanisms but pathogenesis is not clearly understood.

Non-celiac gluten sensitivity needs to be better defined and an optimal diagnostic algorithm is needed.

Larger double-blind RCT studies are needed. Gluten free diet may be reasonable to try in

motivated patients.

Celiac Disease Management Recommendations Consultation with a skilled dietician Education about the disease Lifelong adherence to a GFD Identification and treatment of nutritional

deficiencies Access to an advocacy group Continuous long-term follow-up by a

multidisciplinary team

Thank you!