Jamie S. Barkin, M.D., MACP, MACG, AGAF, FASGEProfessor of Medicine

University of Miami, Miller School of MedicineChief, Division of Gastroenterology

Mt. Sinai Medical Center

Introduction

Celiac disease is a genetically-determined autoimmune condition that can present at any age

It is a permanent intolerance to the gliadin fraction of proteins in wheat, barley and rye

Prevalence 1:100 to 1:150 persons

Caucasians are more at risk than other races

McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450Marmouz F. Eur Ann Allergy & Clin Immunology 2007;39:23-25

Prevalence of Celiac Disease

Healthy population - 1:133

1st degree relatives - 1:18 to 1:22

2nd degree relatives - 1:24 to 1:39

Fasano, et al. Arch Intern Med 2003;163:286-92

Celiac Disease

Three peaks: Infancy Second to third decade of life Fifth to sixth decade of life

Delay in diagnosis – 7 years

Ciclitira PJ. Nature Clinical Practice Gastroenterology & Hepatology 2007 (4);9:483

The Celiac Iceberg

Symptomatic Celiac disease

Silent celiac disease

Latent Celiac Disease

Genetic susceptibility – DQ2, DQ8 Positive serology

Manifest mucosal lesion

Normal mucosa

(Adapted) CDHNF - NASPGHAN

Stages of Celiac Disease

Symptom Serology Histology

Latent - + -

Silent - + +

Diarrhea + ++

Spectrum of Celiac Disease

Biopsy

1%

Villous Atrophy Malabsorption

Atypical/AsymptomaticIEL

Symptoms

Does clinical presentation correlate with degree of villous atrophy in patients with celiac disease?

Classical presentation– diarrhea and weight loss symptoms

Atypical or silent presentation – anemia, osteoporosis or dermatitis herpetiformis

Aim: To evaluate the correlation between the clinical presentation of patients with celiac disease and the degree of villous atrophy

Results: 499 patients, more of whom had atypical or silent celiac

disease than classical presentation – 56% vs. 44%

Clinical presentation did not correlate with the degree of villous atrophy in patients with celiac disease

www.nature.com/clinicalpractice/gasthep

Celiac Disease World-Wide

Iran - common finding among patients labeled as irritable bowel syndrome (11%) in Iran

India - common cause of chronic diarrhea both in children and in adults

Central America/Puerto Rico/South America - under-diagnosed

Conditions more common in celiac disease

Diabetes (type 1 – 5% of CD & up to 10% of juvenile diabetes mellitus

Thyroid disorders (autoimmune or Graves)

Adrenocortical failure (Addison's)

Liver disease (raised transaminases in 40% of new CD and primary biliary cirrhosis)

IgA deficiency

Lymphocytic or microscopic colitis

Down’s syndrome

Unusual neurologial disorders

Dental enamel defects

Turner syndrome

(Adaptation) McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450

Associations of CD

Hematological: IgA – deficiency, hemolytical anemia, thrombopenic purpura

Nephrological: IgA – nephropathy

Hepatic and digestive: primary biliary cirrhosis, Crohn’s disease and colorectal bleeding

Lupus, Sjögren’s syndrome myasthenia, rheumatoid arthritis, polyarthritis

Atopia, asthma, disease of farmer’s lung or poultry breeders

Marmouz F. Eur Ann Allergy & Clin Immunology 2007;39:23-25

Pathophysiology of celiac disease

Malabsorption of nutrients, especially iron, folate, calcium and vitamin D

Increased intestinal permeability may permit entry of other toxins which might induce autoimmune diseases

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Incidence of autoimmune diseases in celiac disease (CD): protective effect of the gluten-free diet

AIM:

To determine which factors modulate the risk of autoimmune disease and to evaluate the effect of gluten-free diet in 924 celiac patients

Results The cumulative risk of autoimmune disease was 8.1% ±1% at

age 15, and 15.7%± 1.5% at age 30

Factors associated with an increased risk were family history of autoimmunity and diagnosis of CD before age 36

Cosnes J, et al. Clinical Gastroenterology and Hepatology 2008;;6:753-758

Incidence of autoimmune diseases in celiac disease (CD): protective effect of the gluten-free diet

(Cont)

Results After CD diagnosis, 55/788 patients developed an autoimmune

disease

The cumulative risk of subsequent autoimmune disease was lower in patients compliant to a gluten-free diet vs. noncompliant patients

The incidence of autoimmune diseases was 5.4 per 1000 patient-years during adherence to a gluten-free diet vs. 11.3 per 1000 patient-years during non-adherence to the diet

Cosnes J, et al. Clinical Gastroenterology and Hepatology 2008;;6:753-758

Factors in celiac disease

Genetic susceptibility

Immune system

Environment - Gluten in diet

Genetics and pathogenesis of celiac disease

Concordance is 75 – 90% in monozygotic twins and 10 – 20% in dizygotic twins

In first-degree relatives the prevalence is 10% and in second-degree relatives it is 2%

Patients with CD (95%) carry the human leukocyte antigen (HLA, HLA-DQ2 or HLA-DRB*4 DQ8)

McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450

Non-dietary factors

Infections Viral infections

● Sequence homology between -gliadin and adenovirus type 12 & 7, rubella and human herpes-virus 1

Parasitic infestations● sequence homology between -gliadin and

plasmodium yoelli Other ?

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Dietary Factors

Wheat – (15% protein, 75% starch)

Glutenin (alcohol insoluble)

Gluten

Gliadin(alcohol soluble) Prolamine

Rye prolamines – secalines

Barley prolamines – hordeins

Oats are safe

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Mucosal events

Epithelial cell infiltration increased IEL’s – (>90% CD8, <10% CD4) increased mucosal / T cells (nl <10%) role of / cells in celiac disease is unknown

Mucosal surface alterations loss of epithelial cells proliferation of crypt epithelial cells

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Humoral response in celiac disease

Humoral response Enhanced antibody production

Anti-tissue transglutaminase Anti-gliadin ? Other auto-antigens (anti-actin)

Mechanism of antibody production unknown

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Expanded Definition of celiac disease

Celiac disease is an autoimmune condition Occurs in genetically susceptible individuals DQ2 and/or DQ8 positive HLA haplotype is

necessary but not sufficient A unique autoimmune disorder because:

Both the environmental trigger (gluten) and the auto-antigen (tissue transglutaminase) are known

Elimination of the environmental trigger leads to a complete resolution of the disease

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Celiac Disease and autoimmunity

Prevalence of autoimmune disorders in celiac disease related to duration of gluten exposure Diagnosed before 2 years of age: 5% Age 2-10 years: 17% Greater than age 10 years: 24%

Increased incidence of autoimmune disease in patients with IDDM and ‘silent’ celiac disease and their first-degree relatives who were EMA+

Ventura et al. Gastro 1999; Not, Diabetologia 2001

Prevalence of celiac disease is higher in other autoimmune conditions

Type 1 diabetes mellitus

Thyroiditis

Arthritis

Autoimmune liver diseases

Sögren’s syndrome

Idiopathic dilated cardiomyopathy

IgA neuropathy

3.5 – 10%

4 – 8%

1.5 – 7.5%

6 – 8%

2 – 15%

5.7%

3.6%

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Visible Iceberg of CD

Diarrhea

Abdominal pain

Weight loss

Constipation

Bloating

Presenting features of celiac disease Adults

Diarrhea, altered bowel habit including constipation Abdominal pain, dyspepsia, bloating Aphthous ulcers – mouth Anemia (fe or folate and rarely vitamin B-12) Weight loss Dermatitis herpetiformis Malabsorption, edema Osteoporosis, low impact fracture

McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450

Invisible Part of the Iceberg

Hematological: iron deficiency anemia

Rheumatologic: demineralization, arthralgias fractures

Neurological: peripheral neuropathy (lack of), epilepsy (and cerebral calcifications) ataxia (vitamin E deficiency?), Migraine

Digestive: stimulating functional, mouth ulcers, unexplained increase of transaminases and rare severe hepatopathy

Gynecological: infertility, amenorrhea, fetal hypotrophy, miscarriages

Marmouz F. Eur Ann Allergy & Clin Immunology 2007;39:23-25

Increased overall mortality in adult life

Secondary to increased: Autoimmune diseases

Osteoporosis

Liver diseases

Cancer

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COMPLICATIONS

Potential Nutritional Complications in Untreated Celiac Disease

Low IronLow folateLow vitamin B-12Low vitamins ADEKLow thiamine

Low niacinLow B6 (rare)Low beta-caroteneLow zincEssential fatty acid deficiency

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Potential Nutritional Complications in Untreated Celiac Disease

Prolonged PTHypocalcemiaElevated PTHIncreased alkaline phosphatase

HypophosphatemiaHypomagnesaemiaRe-feeding syndrome

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Iron deficiency anemia resistant to oral iron

One of the most common non-GI manifestation in adult studies

5 – 8% of adults with unexplained iron deficiency anemia have celiac disease

In children with newly diagnosed celiac disease Anemia is common Little evidence that celiac disease is common in children

presenting with anemia

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Bone Disease in Celiac Disease

Arthritis Osteoporosis Osteopenia Osteomalacia Rickets

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Bones and Celiac Disease

CD presenting with classic malabsorptive symptoms was the association with bone disease, particularly osteomalacia (Bennet et al, 1932)

Reduced bone mineral density, osteopenia or osteoporosis in 20 – 50% of the patients newly diagnosed with CD (Butcher, et al 1992; Corazza, et al 1995, 1996; Mc Farlane et al, 1995; Kemppainen et al, 1999; Cellier et al 2000; Meyer et al 2001)

The consequences of these bone changes are probably an increase in aches and pains

McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450

Cont

Bones and Celiac Disease

Increased fracture is reported , but the risk is small

Patients who presented subclinically with anemia or osteopenia or just on screening, the fracture risk is not increased compared with the controls

BMD does improve with a GFD but may not return to that seen in a matched population (Corraza et al. 1995; McFarlane et al 1995; Sategna-Guidetti et al. 2000; Pazianas et al. 2005)

Risk of cancer in celiac disease

Increased DecreasedDefinite*

Non-Hodgkin's lymphoma – T>BSmall bowel adenocarcinoma

PossibleEsophagusMelanomaLarge bowelLiverOropharyngealPancreas

*Diminishes with time from diagnosis except NHL & only in those with dietary compliance

Breast

Lung?

(Adaptation) McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450

“Hepatitis” and Celiac Disease

Evidence for elevated serum transaminases (ALT, AST) in adults with untreated celiac disease

● Up to 9% of adults with elevated ALT, AST may have silent celiac disease

● Liver biopsies in these patients showed non-specific reactive hepatitis – may simulate NASH

● Liver enzymes normalized on gluten-free diet

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Celiac disease screening amongst women of reproductive age

A Swedish cohort study compared 2078 births by women diagnosed with celiac disease prior to or after the birth of an infant with the background child-bearing population

Result: Undiagnosed maternal celiac disease at birth was

strongly linked to low or very low infant birth weight, lower placental weights and higher Cesarean section rate

Ludvigsson JF et al. Gastroenterology 2005;129:454-463

Dermatitis Herpetiformis

Garioch JJ et al. Br J Dermatol 1994;131:822-6Fry L. Baillieres Clin Gastroenterol 1995;9:371-93

Reunala T, et al. Br J Dermatol 1997;136:315-8

● Erythematous macule >urticarial papule > tense vesicles

● Severe pruritus

● Symmetric distribution

● 90% no GI symptoms

● 75% villous atrophy

● Gluten sensitive

Diagnostic principles of celiac disease

Confirm diagnosis before treating Diagnosis of celiac disease mandates a strict gluten-free

diet for life following the diet is not easy QOL implications

Failure to treat has potential long-term adverse health consequences Increased morbidity and mortality

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Role of serological tests in Celiac Disease

Identify symptomatic individuals who need biopsy

Screening of asymptomatic “at risk” individuals who need a biopsy

Supportive evidence for the diagnosis

Monitoring dietary compliance

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Serological tests

Antigliadin antibodies (AGA) Antiendomysial antibodies (EMA) Anti-tissue transglutaminase

antibodies (TTG) First generation (guinea pig recombinant Second generation (human recombinant)

HLA typing

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Serological Test Comparison

Sensitivity % Specificity %

AGA-IgG

AGA-IgA

EMA (IgA)

TTG (IgA)

69 – 85

75 – 90

85 – 98

90 - 98

73 – 90

82 – 95

97 – 100

94 – 97

Farrell RJ, Kelly CP. Am J Gastroenterol 2001;96:3237-46

Anti-gliadin antibodies (AGA)

Sensitivity and specificity do not exceed 80%

The specificity of AGA IgA is approximately 50%

False positive results can be found in patients with esophagitis, gastroenteritis, inflammatory bowel diseases

Basso D, et al Lupus 2006;15:462-465

Serology diagnosis of celiac disease

Tissue transglutaminase is the serological test of choice for the diagnosis of CD

Selective IgA deficiency is found in 2-3% of individuals with CD and affects not only tTg IgA antibodies but also EMA and AGA IgA antibodies

Both IgA and IgG AGA antibodies are present in the sera of patients with CD, although they are not specific because gliadin crosses the normal gut mucosa, and approximately 5 -10% of the healthy population will be positive, particularly older individuals

McGough N, et al Proceedings of the Nutrition Society 2005;64;434-450

Biopsy diagnosis of celiac disease

Histological Features: Increased IEL’s (>30/100 enterocytes) Loss of nuclear polarity Change from columnar to cuboid Lamina propria cellular infiltrate Crypt elongation and hyperplasia Increased crypt mitotic index Progressive villous flattening

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Role of “Routine” Small Bowel Biopsy at Endoscopy

Current practices by pediatric GI physicians

Rationale: Celiac disease is common and endoscopic appearance may look

normal Era of open access endoscopy

Routine biopsy in high-risk groups Family members Chronic liver disease IBS, IDDM, IBD, Sjögren syndrome Down’s syndrome Patients with atypical symptoms

Mucosal Differential Diagnosis of Immunopathology

Celiac Giardiasis Milk intolerance Tropical sprue GVHR

Marsh, Gastroenterol 1992;102:330-354

Two main problems when considering screening

~25 – 30% of individuals with positive screening serological tests may have normal biopsies. It is unclear whether these individuals have early or mild celiac disease, false positive tests or variable production of autoantibody of unclear prognostic value

Compliance with gluten-free diet is poor when symptoms are mild or absent and when diagnosis is made beyond childhood

Liu E, et al Clin Gastroenterol Hepatol 2003;(1):356-362

TREATMENT

Gluten-Containing Grains to Avoid

Wheat

Wheat Bran

Wheat Starch

Wheat Germ

Flour/Meal

Semolina

Spelt

Bulgar

Couscous

Durum

Einkorn

Barley

Barley Malt/Extract

rye

Filler

Graham flour

Kamut

Matzo

Emmer

Faro

Triticale

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Ingredients that may contain gluten

Seasonings and spice blends or mixes Modified food starch Malt/malt extract/flavoring Modified hop extract and yeast-malt sprout

extract Dextrin Caramel color

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Other items to consider

Lipstick/gloss/balms Mouthwash/toothpaste Play dough Stamp and envelope glues Vitamin, herbal and mineral preparations Prescription or OTC medications

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Gluten-Free Grains and Starches

AmaranthArrowrootBuckwheatCornFlaxMilletMontinaOats*

PotatoQuinoaRiceSorghumTapiocaTeffFlours made from nuts, beans and seeds

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*for possible cross-contamination with gluten -containing grains

Can oats be taken in a gluten-free diet (GFD)? A systematic review

Results 10 studies involving 165 patients

Only 1 patient was shown to have histological damage as a result of consuming oats

Conclusions Celiac patients can, to some advantage, include oats in a GFD

Recommend adding oats to their GFD when they are established on a conventional GFD

Garsed K, Scott BB. Scand J Gastroenterol 2007;42:171-78

Safe Ingredients

Starch

Maltodextrin Made from cornstarch, potato starch, or rice starch,

but not from wheat

Vinegar and alcohol Distilled vinegar and distilled spirits are gluten-free,

however avoid malt vinegar and malt beverages (e.g. beer)

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Health beliefs of adults with celiac disease

Survey of 100 people in celiac disease support group (Buffalo, NY) Number of people who agreed with following statements:

”If I eat less gluten I will have less intestinal damage” (51%)

“I’ve lived this long eating gluten, how much will the gluten-free diet really help me now?” (33%)

“my doctor should be the one to tell me when I need follow-up testing” (26%)

“Scientist/doctors still haven’t proven that gluten really hurts them” (16%)

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Dietary adherence: A common Problem

Only 50% of Americans with chronic illness adhere to their treatment regimen including: Diet Exercise Medication

Dietary compliance can be the most difficult aspect of treatment

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Barriers to Compliance

Time pressure – time to plan, prepare food is longer

Planning – work required to plan meals

Competing priorities – family, job, etc.

Assessing gluten content in foods/label reading

Eating out – avoidance, fear, difficult to ensure food is safe

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Barriers to Compliance

Social events – not wanting to look/be different

Support of family and friends – “just a little bit – it won’t hurt you”

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Treatment of Celiac Disease

Gluten-free diet Compliance problems due to palatability,

variations in food labeling and possible cross-contamination of other foodstuffs by gluten are common

Ludvigsson JF et al. Gastroenterology 2005;129:454-463

Factors that Improve Adherence

Knowledge about the gluten-free diet Understanding the risk factors and serious

complications can occur to the patient Ability to break down big changes into smaller steps –

ability to simplify or make behavior routine Ability to reinforce positive changes internally Positive coping skills Ability to recognize and manage mental health issues External test results are motivational, especially in

asymptomatic individuals

NASPGHAN

Possible Causes of GI Symptoms on a Gluten-Free diet

Food intolerance to fructoseSorbitolOlestraGuar gumsAntibioticsLactose

Alternate flours made from beans or nutsFood allergens such as milk, protein, soy, nuts, egg, corn

Foods high in salicylates and amines

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Dietary triggers of IBS

Fermentable Oligosaccharides, Disaccharides, Monosaccharide and Polyols (FODMAP)

FODMAPs can include fructose and lactose, polyols (such as sorbitol) and fructo-oligosaccharides (fructans)

Major dietary FODMAPs include fructose and fructans; fructose are fruits, honey and high fructose corn syrup, and of fructans they are wheat and onions

Shepherd SJ, et al Clinial Gastroenterology & Hepatology 2008;6:765-771

Lactose Intolerance & Celiac Disease: Incidence

Secondary lactase deficiency is estimated to be 20% - 40%

Increasing lactose intolerance with delayed diagnosis

Increased incidence in patients with GI symptoms in celiac disease

Decrease calcium and vitamin D intake in lactose intolerance

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Causes of poor response to gluten-free diet

Wrong diagnosis Gluten ingestion* Lactose intolerance* Pancreatic insufficiency* Microscopic colitis* Bacterial overgrowth* Other food intolerances (fructose, milk, soy) Collagenous colitis

IBD Collagenous sprue Ulcerative jejunitis Autoimmune enteropathy Adenocarcinoma EATL Refractory sprue (+/- clonal T cell populations

*common Peter Green, M.D.

Resources

Reputable websites Celiac.com (www.celiac.com) National Institutes of Health (www.niddk.nih.gov) American Dietetic Association (www.eatright.org)

Local Support Groups Celiac.com (www.celiac.com)

National Support Groups The Gluten Intolerance Group – GIG (www.gluten.net) Celiac Disease Foundation – CDF (www.celiac.org)

Research and Information Center for Celiac Research (www.celiaccenter.org)

Resources

Cookbooks Hagman, Bette, “The Gluten-Free Gourmet Cooks Fast and

Healthy” Saros, Connie, “Wheat-free Gluten-free Cookbook for Kids

and Busy Adults” Books and Magazines Case, Shelly, “Gluten-Free Diet: A comprehensive

Resource Guide” Gluten-Free living Sully’s Living Without (www.livingwithout.com)

Product information www.glutenfreemall.com

NSPGHAN

Selected support groups and websites

Children’s Digestive Health and Nutrition Foundation

National Institutes of Health

Gluten intolerance Group

Celiac Foundation

Celiac Sprue Association

www.celiachealth.org

www.nlm.nih.gov/medlineplus/celiacdisease.html

www.gluten.net

www.celiac.org

www.csaceliacs.org

Liu E, et al Clin Gastroenterol Hepatol 2003;(1):356-362

Dietary Factors

33 amino acid peptide in gliadin contains critical epitopes – high in glutamine and proline

Resistant to digestion in lumen

Penetrates epithelial barrier

Modified by the enzyme tissue transglutaminase Deaminates glutamine residues to glutamic acid

Resulting higher affinity binding to HLA DQ2 molecule on the surface of antigen-presenting cells

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Long-term follow-up of 61 celiac patients diagnosed in childhood: Evolution toward latency is possible on a normal diet

Introduction:

The question still remains as to whether the maintenance of a life-long gluten-free diet is necessary in all celiac children or whether in some of them a gluten-containing diet can be safely reintroduced

Aim:

To retrospectively analyze the clinical and biological status of adult celiac patients diagnosed in childhood, who remained on a normal diet after gluten challenge and were clinically silent

Matysiak-Budnik T, et al Gut 2007;56:1379-1386

Long-term follow-up of 61 celiac patients diagnosed in childhood: Evolution toward latency is possible on a normal diet

(Cont)Results: 61 patients had resumed a normal diet and were asymptomatic

48 showed different degrees of villous atrophy (silent CD); 13 had no detectable atrophy (latent CD) on duodenal biopsies

Conclusion: Long-term latency developed in about 20% of CD patients who

remained symptom free after gluten reintroduction

Silent celiac – risk of osteoporosis necessitates gluten-free diet

Matysiak-Budnik T, et al Gut 2007;56:1379-1386

Budesonide in the treatment of refractory celiac disease

POP 29 patients (72% female) received budesonide for a mean of

6.7 ± 8.5 months

Results 12 of 15 had complete response to Budesonide

Conclusion Response occurred in those who had refractory disease and in

those with type II disease, irrespective of the presence of microscopic colitis (N = 7)

Brar P, et al. Am J Gastroenterol 2007;102:2265-2269

Budesonide and concomitant medication use in relation to budesonide response

Therapy No. of Complete Moderate Poor

patients Response Response Response

Budesonide alone 15 12 3

Budesonide + S 3 1 1 1

Budesonide + S + A 7 5 2

Budesonide + A 4 3 1

Total 29 (100%) 55% 21% 24%

S – systemic steroids; A - azathioprine

Brar P, et al. Am J Gastroenterol 2007;102:2265-2269

Response to hepatitis B vaccination in patients with celiac disease

Non-responsiveness to hepatitis B virus (HBV) vaccination is related to genetic features

Strong relationship between CD and these human leukocyte antigen (HLA) genotypes

Responsiveness to HBV vaccination was observed in 17 (68%) CD patients and all (100%) control subjects (P = 0.006)

Ahishali A, et al. Dig Dis Sci 2008;53:2156-2159