# Presentation: 815446

## Introduction to Celiac Disease  

- Joseph Murray
- The Mayo Clinic
- Rochester, MN

## Outline

- What is celiac disease
- What causes it
- Who gets it
- Treatment
- Complications and compliance
- Prognosis

## Food Intolerances

## Anatomy of the Small Intestine

## Normal Villi 

## What is Celiac Disease?

- It is a inflammatory state of the small intestine that occurs in genetically predisposed individuals and resolves with exclusion of dietary gluten.

- Normal

- Celiac
- Disease

## What Causes it? 

## Pathogenesis of Celiac Disease

**HLA**

**Environment**
**Gluten**

**Immune Response**

- Inflammation

## Genetics of Celiac Disease

- Strong family predisposition
- Monozygous twins (80%), siblings (10%) kids (5-10%)
- Strong HLA association  (DQ2 and DQ8)
- Non HLA genes suspected but not confirmed
- Certain chromosomal disorders:
- Down’s, Turner’s and Williams syndrome

## Slide 10

## Wheat Kernel

- Bran = fibre
- Endosperm = starch and protein
- Germ = protein and lipid
- Proteins ( gluten)
- gliadins
- glutenins

## Wheat Protein 

- Uniquely high in certain amino acids
- Prolines and glutamines   pQPQLPY
- Glutamines can cross-linked to give the grain its resiliency and the glue or “gluten” that gives bread shape
- Proline  sequences  form helices resistant to digestion  **Shan, Science 2002**

## Gluten and DQ2

- Gliadin molecules are presented by the DQ2/8 molecules to the T-cells in the gut
- Certain gliadin molecules have a greater affinity than others
- Peptides may be processed or altered to make them more antigenic
- Immunodominant peptides are digestion resistant  ( Proline twists)

## Role of Tissue Transglutaminase

- Enzyme present in gut
- Autoantigen recognized by IgA in active CD
- Released by fibroblasts in inflammation
- Cross links cystine residues
- Alters gliadin by de-amidating glutamine to glutamate
- The de-amidated molecule fit perfectly into the binding grove of DQ2 or DQ8

## Pathogenesis of Celiac Disease

## Villous and Cell Structure 

- Villous and Cell Structure

- Fasano, et.al.

- Zonulin

- Anti-Actin

- Metalloprotease

- Endothelial
- injury

## Increased Paracellular  Permeability 

- Increased Paracellular  Permeability

- Gliadin

**Antigen **
**Presenting **
**Cell**

- Increased Zonulin release

- Fasano, 2002

## Triggers for Celiac Disease

- Gluten in the infant diet
- Age at introduction
- Amount of gluten
- Other events
- Pregnancy
- Infections
- Surgeries

## Evolutionary Collision 

**Evolutionary Collision**

- Kasorda, 1992

**Wheat**

**Human Immune System**

## How Does It Present? 

- And Who Gets It?

## Classical Celiac Disease

- <date/time>

***NASPGHAN***

## Presentation in Children

- Onset after introduction of gluten
- Age 6 months to 7 years
- Failure to thrive
- Abdominal distension
- Anorexia
- Diarrhea
- Steatorrhea
- Anemia
- Growth failure
- Vitamin deficiencies

**Notes:**
This is a picture of a 15 month old child with undiagnosed celiac disease.  This child had classic symptoms of poor growth, severe diarrhea, and abdominal distention.  Despite this “classic” presentation, this child saw 4 pediatricians before being referred to a pediatric GI who made the diagnosis of celiac disease.  The time period from presentation of symptoms to diagnosis was 9 months.

## Gastrointestinal Presentation in Adults

- Age: May present at any age
- Symptoms may include:
- Abdominal pain
- Heartburn, nausea and vomiting
- Anemia and fatigue
- Malabsorption (steatorrhea rare)
- May have constipation

- Murray et al. AJCN, 2004

**Notes:**
The diagnosis of celiac disease is increasingly being made in adults.  In the adult GI form, patients still have GI symptoms, but outside the classic childhood age range.  Peaks appear to occur at puberty and within people in their 40’s and 50’s.  A recent study from Olmstead County, Minnesota (Murray et. al) showed the mean age of diagnosis was 45 years of age and 90% of all new cases were adult.  Adults may often have upper GI as opposed to lower GI symptoms with heartburn, nausea, and vomiting.
Adults may present with constipation instead of diarrhea.

## Gastrointestinal Presentation in Adults

- May mimic other GI disorders:
- Lactose intolerance
- Irritable Bowel Syndrome
- Inflammatory Bowel Disease

**Notes:**
Adults with undiagnosed celiac disease often get labeled with other, more common diseases.  They are, in fact, lactose intolerant, due to decreased amounts of the lactase enzyme in the damaged gut.  However, this is a SYMPTOM of celiac disease, rather than the disease itself.
The symptoms of irritable bowel syndrome are identical to that of celiac disease.  5% of IBS patients may have celiac disease (Sanders et al., Lancet 2001).  However, the recommended treatment for IBS, increasing dietary fiber, is detrimental to the undiagnosed celiac patient. 
Because of the patchy  nature of inflammation seen on the small intestinal biopsy, celiac disease may be confused with Crohn’s disease.  However, an astute clinician and pathologist should be able to differentiate the two.  Crohn’s and celiac disease, both autoimmune diseases, can unfortunately co-exist in the same patient.

## Specific Deficiencies

- Fat soluble vitamins: D,E,A,K
- D; osteomalacia and myopathy*
- E; Neurological syndromes
- A; night blindness
- K; bleeding, epistaxis
- Iron*
- Folate
- B12
- Zinc, B6, selenium and others

- * often isolated

## Extra-intestinal Presentation

**May involve:**
- Musculoskeletal System (joint pain, osteoporosis)
- Reproductive (infertility, delayed puberty, spontaneous recurrent abortions)
- Hematologic (anemia)
- Hyposplenism
- Dentition (enamel defects)

**Notes:**
Celiac disease can be confusing to the clinician, as it may present outside the GI system in children or adults.
In the musculoskeletal system, patients may complain of joint pain or have short stature, osteomalacia or osteoporosis.
Both women and men have infertility secondary to celiac disease.  It is unclear how much trace vitamin and mineral deficiencies play a role in this.
Untreated patients with celiac disease often have anemia, usually due to iron deficiency.  A macrocytic anemia can be seen in advanced disease due to B12 and/or folic acid malabsorption.
Hyposplenism is present in 30-76% of adults with celiac disease. This has been determined by splenic function studies which have included sulphur colloid Tc scans, labeled red cell clearance studies and “pitted” red cell counts. The severity is correlated with older age of diagnosis, duration of gluten ingestion, and there are suggestions of improvement with a gluten-free diet. This is the indication for adult patients at diagnosis to receive pneumococcal vaccination. Patients with celiac disease have an adequate response to the vaccine.
Dental enamel defects, which are vertical linear defects in the secondary teeth, have been well described in celiac disease.  Often these patients have cavities in unusual locations, such as in the incisors, and have sealants placed on their teeth.

## Fe-Deficient Anemia

**Most common non-GI manifestation in some studies**
**5-8% of adults with unexplained iron deficiency anemia have Celiac Disease**
**Especially in those resistant to oral iron**
**5-15% of patients undergoing endoscopy for fe deficiency anemia have celiac disease**
**30-50% of patients getting EGD for anemia do not get duodenal biopsies!**** **

- Vogelsang, 98; Grisolano, 2004

- Harewood, 2003

## Osteomalacia	

**Osteomalacia**

**Notes:**
Osteomalacia in a celiac patient showing pseudofractures of the pelvis (arrows).  Patient was 45 years old and presented with bone pain and proximal muscle weakness (for over 2 years) in the absence of overt GI symptoms.  Elevated alkaline phosphatase and absence of Vitamin D stores were seen.

## Extra-intestinal Presentation

- Neurologic and psychiatric syndromes
- neuropathy, ataxia, seizures, dementia
- Fibromylagia, Chronic Fatigue Syndrome
- Skin and mucous membranes (rash, aphthous ulcers)
- Dental enamel defects
- Dermatitis herpetiformis (caused by gluten)

**Notes:**
Patients with celiac disease have 20 times the incidence of seizures and an increased occurrence of depression, schizophrenia, and dementia.  Also reported are migraines, peripheral neuropathy and associations with cerebral calcifications (which respond to a gluten-free diet), and so-called “gluten ataxia”.  Children with this disease are often irritable, anorectic, and demonstrate increased separation anxiety.  It is unclear what the association is with celiac disease and ADHD and autism, although anecdotal reports suggest improvement with the conditions on a gluten-free diet.
Because patients with celiac disease often have multisystemic complaints (also known as a “positive review of systems”), they are often diagnosed with hypochondriasis or a mental illness.
Dermatitis Herpetiformis, which is an itchy, scaling, blistering rash, usually occurs on the face, elbows, back, buttocks and knees.  It is diagnosed by skin biopsy.  Patients with a + skin biopsy for DH do not need an intestinal biopsy to confirm celiac disease, as DH is pathognomonic for celiac disease.  
Patients with celiac disease may also suffer from  recurrent aphthous stomatitis, urticaria, and psoriasis.

## Dermatitis Herpetiformis 

**Dermatitis Herpetiformis**** **

## Associated Conditions

- Other Autoimmune Diseases
- Type 1 Diabetes Mellitus – 3.5-7%
- Thyroiditis – 4%
- Arthritis – 1.5-7.5%
- Primary Biliary Cirrhosis – 6%
- Congenital Disorders
- Down’s Syndrome – 4-14%
- Turner Syndrome – 4-8%
- IgA Deficiency – 7%
- Relatives 5-20%

**Pietzak et al. Nutrition in Clinical Practice  2001**

**Notes:**
Children and adults with other associated conditions are at higher risk for celiac disease than the general population.  These include patients with other autoimmune diseases (such as IDDM, thyroid disease and PBC), congenital disorders, and relatives of biopsy-proven celiacs.

## Celiac Disease: Asymptomatic and Latent Forms

- Asymptomatic
- No apparent symptoms or associated diseases
- May be first or second-degree relatives of patients with biopsy proven celiac disease
- Latent
- Positive serology with negative small bowel biopsies

**Notes:**
Some patients have no symptoms of celiac disease.  They are often “picked up” at mass screenings, and are often relatives of celiac patients. 
Patients with latent disease will often progress to have positive biopsies later in life.

## Celiac Disease: Epidemiology

- First identified in Europe
- Prevalence is 1 in 90-300
- Diagnosis rate is lower ( 1:2000)
- One of most frequent genetic based diseases
- Studies in Latin American, African, & Asian countries indicate CD is worldwide
- Worldwide average prevalence estimated ~ 1%

**Fasano, et al.**
**Gastroenterology 2001**

**Notes:**
Celiac disease was first described in Europe.  A number of European studies over the past 3 decades have defined the prevalence of this disease and its genetic background.  Screening studies indicate the European prevalence is estimated to be 1 in 130-300.  However, the rate of diagnosis of celiac disease in these countries is much lower.
Additionally, epidemiological studies conducted in other areas of the world with genetic and grain consumption risks indicate that celiac disease is under diagnosed.  These studies estimate that the prevalence worldwide is 1:266.
Until recently, studies on the incidence and prevalence of celiac disease in the U.S. population have been scarce.  

## Age and Sex Adjusted Incidence Rates Among Olmsted County Residents

**Calendar Year By Decade**

**1950-1959**

**1960-1969**

**1970-1979**

**1980-1989**

**1990-1999**

**2000-2001**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**Celiac**

**DH**

**Age and Sex Adjusted Incidence Rates Among Olmsted County Residents**

**Incidence/100,000**

## Crude Incidence of Celiac Disease in Olmsted Co.

**Age at diagnosis**

**Incidence/100,000**

**0**

**1**

**2**

**3**

**4**

**5**

**0-3**

**4-18**

**19-44**

**45-64**

**65+**

**Females**

**Total**

**Males**

**Crude Incidence of Celiac Disease in Olmsted Co.**

**1950-2001 by Diagnosis age**

## Celiac Icebergs (circa 1996)

**CP1002147- 2**

**Celiac Icebergs (circa 1996)**

**U.S.A.**

**Finland**

**Ireland**

**Denmark**

**Sweden**

**Italy****‡**

**0.2**

**2.7**

**2.5**

**0.46**

**1.0**

**0.8**

**4.0**

**7.7**

**8.2**

**5.3**

**5.0**

**1.0**

*****

*******Active case finding**

** ****‡**** ****Regional**** ****variation**

## Natrona County, Wyoming 

- ~ 20 cases in population of 40,000
- Annual health fair screening
- 32/4036 had positive TTg _and_ EMA
- 15/16 biopsied cases proven to have CD
- 1: 126 adults with celiac disease
- 1/2 had GI symptoms mostly constipation
- Two had family members with CD

## Making the Diagnosis

- Suspicion
- Serology tests
- Tissue transglutaminase antibodies
- Endomysial antibodies
- Intestinal biopsy ( gold standard)
- Response to a gluten free diet

## Celiac Disease Pathology

**Celiac Disease Pathology**

- Intraepithelial
-  lymphocytes

- Crypt Hyperplasia

- Increased
- lymphocytes
- macrophages,
- plasma cells and
- eosinophils

- Villous atrophy

## 0

**0**

**1**

**2**

**3**

**4**

**CP1027863- 2**

**Marsh Classification **

**Notes:**
Marsh stages of celiac disease 

## Slide 43

## Treatment of Celiac Disease

- Gluten Free Roulette

## Nuts and Bolts of a Gluten Free Diet 

- Avoid the offending grains
- Wheat
- Barley
- Rye
- Wheat-like grains
- Spelt
- Kamut
- “Most corn or rice commercial cereals are _NOT_ GF

## How Much Gluten is Too Much?

- Threshold for damage is 20-100 mgs/day?
- Symptoms are not a good indicator
- tTg antibodies positive > 1gram/day
- Cheating > 1/month ---> chronic injury
- Variable sensitivity

## Codex Alimentaris  2004

- Naturally gluten free foods:  20 PPM
- Rendered gluten free foods: 200 PPM
- Draft document
- Some countries allow gluten-reduced wheat starch
- New tests for gluten contamination

## Non-Responsive Celiac Disease

- Diet, diet and diet!!! ( > 50%)
- Lymphocytic colitis
- Pancreatic insufficiency
- ? Bacteria overgrowth
- True refractory sprue

## Potential Sources of Contamination

- Commercial cereals
- Eating out
- Communion wafers
- Lipstick
- Airborne flour/ starch
- “Soy” sauces made with wheat
- Mislabeled or unlisted ingredients
- Medication

## Ingredients to Question(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

***NASPGHAN***

## Complications Associated with Untreated Disease

- Mortality rate in patients with untreated celiac disease is **TWO FOLD GREATER** at every age
- Gastrointestinal malignancies
- Osteoporosis
- Stunted growth
- Infertility
- Chronic ill health
- All can be prevented with early treatment

**Corrao et al.. Lancet 2001**

**Notes:**
The primary etiology for increased mortality is due to the association with gastrointestinal malignancies, primarily intestinal lymphoma, which has been reported in 10-15% of adult patients with celiac disease who have been non-compliant with the gluten-free diet.
Osteoporosis is due to the malabsorption of calcium and vitamin D in the later stages of the illness.  Osteomalacia is thought to begin in childhood.  Normal bone density is achievable if the disease is caught early.  However, it may become irreversible in advances cases.
In regards to chronic ill health, an adult patient with celiac disease usually sees several different physicians over the course of several years before getting the correct diagnosis.  On average, it takes about 11 to 12 YEARS from the time an adult complains of symptoms to the time of diagnosis of celiac disease.  
The complications of malignancy, osteoporosis and the delay in time to diagnosis significantly impact health care costs.

## Dangers of Non-Compliance

- Increased mortality **Holmes et al. 1989 Corrao et al. **
- Osteoporosis  Cellier
- Lymphoma
- Other cancers
- Psychological effects hallert

## Enteropathy Associated Lymphoma

- Celiac
-  disease

- Lymphoma

## Does Silent Celiac Disease Matter?

- Are those identified less sick that clinically diagnosed CD
- What is the benefit or negative effects of a GFD in people found by screening
- Are they any less likely to comply with a gluten free diet?
- Affect mortality?

## “What some call health, if purchased 

- “What some call health, if purchased
- by perpetual anxiety about diet,
-  isn’t much better than tedious disease”
- 		*George Dennison Prentice, 1860*

## The Future

- Bioengineer wheat free of antigenic moieties
- Block DQ interaction with gluten
- ? Block TTg*
- Predigest peptide fragments
- Prevent or reverse sensitivity
- Block gliadin effects on permeability
- Block de-amindation
- Re establish tolerance

- * TTG-IgA block the active site

## Predigestion Strategy?

## Summary

- Celiac disease is common
- Largely unrecognized until recently
- Many challenges in treatment
- Gluten free diet not simple
- Widespread use of grain proteins in food
- Food ingredient source identification
- Regulation ( Food Allergy Act of 2004)
- Defining acceptable thresholds and verification

## Another Food Safety Issue? 

- Another Food Safety Issue?

- Camp Ripley, MN