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
CDHNF - NASPGHAN
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 ?
CDHNF - NASPGHAN
Dietary Factors
Wheat – (15% protein, 75% starch)
Glutenin (alcohol insoluble)
Gluten
Gliadin(alcohol soluble) Prolamine
Rye prolamines – secalines
Barley prolamines – hordeins
Oats are safe
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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%
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
Potential Nutritional Complications in Untreated Celiac Disease
Prolonged PTHypocalcemiaElevated PTHIncreased alkaline phosphatase
HypophosphatemiaHypomagnesaemiaRe-feeding syndrome
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
Bone Disease in Celiac Disease
Arthritis Osteoporosis Osteopenia Osteomalacia Rickets
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
Serological tests
Antigliadin antibodies (AGA) Antiendomysial antibodies (EMA) Anti-tissue transglutaminase
antibodies (TTG) First generation (guinea pig recombinant Second generation (human recombinant)
HLA typing
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
Other items to consider
Lipstick/gloss/balms Mouthwash/toothpaste Play dough Stamp and envelope glues Vitamin, herbal and mineral preparations Prescription or OTC medications
CDHNF - NASPGHAN
Gluten-Free Grains and Starches
AmaranthArrowrootBuckwheatCornFlaxMilletMontinaOats*
PotatoQuinoaRiceSorghumTapiocaTeffFlours made from nuts, beans and seeds
CDHNF - NASPGHAN
*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)
CDHNF - NASPGHAN
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%)
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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”
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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
CDHNF - NASPGHAN
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
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