Gluten Enteropathy

Epidemiology

Affects both adults and children
May present as Failure to Thrive in infants
Older patients over age 60 years represent 20% of cases
Prevalence: 1 per 120-300 in United States and Europe (0.5 to 1%)
1. Prevalence 2 to 4% in those with chronic abdominal symptoms
More common in white patients and rare in asian patients
More common in women (75% of adult cases)
Family History increases risk
1. Monozygotic twins: 75% concordance rate
2. First degree relatives: 10% have Celiac Disease
3. Second degree relatives: 3-6% have Celiac Disease

Pathophysiology

Small Bowel exposure to Antigens in cereal grains (rye, wheat, barley)
Immunologic disorder of Small Bowel
1. Abnormal T Cell and IgA and IgG Antibody response
2. Enhanced immunogenic response to gliadin (Alcohol-soluble portion of gluten) at lamina propria
3. Results in intense local inflammation at villous resulting in villous atrophy
4. Significantly decreases absorptive surface
Related to HLA Class II DQA1*0501 and DQB1*0201 (HLA-DQ2 and HLA-DQ8)
1. Associated with other Autoimmune Conditions as below
2. Absence of both HLA-DQ2 and HLA-DQ8 makes the diagnosis of Celiac Sprue highly unlikely
  1. However these haplotypes are present in more the 25% of the general population
  2. Only 4% of patients with HLA-DQ2 or HLA-DQ8 develop Celiac Sprue

Risk Factors
Adults

See Associated Conditions below
See epidemiologic factors and above
Family History
1. See HLA-DQ2 and HLA-DQ8 genetic association as above
2. First degree relatives (esp. monozygous twins): 10% affected
3. Second degree relatives: 3 to 6% affected

Risk Factors
Children

See Associated Conditions below (includes chromosomal abnormalities)
Risk factors
1. Ceserean delivery
2. Rotavirus infection
3. Gluten exposure before age 5 years
  1. Previously thought that gluten exposure ages 3 to 7 months was protective
  2. Later studies show increased risk if exposed under age 5 years and no protective effect window
Protective factors
1. Breast Feeding (disproven)
  1. Longer duration of Breast Feeding including the time of first gluten exposure was thought protective
  2. Later studies do not demonstrate Breast Feeding protection against Celiac Disease
References

Associated Conditions

Chromosomal abnormality
1. Turner's Syndrome (6%)
2. Down Syndrome (8%)
3. Williams Syndrome (8%)
Autoimmune Conditions
1. Type I Diabetes Mellitus (2-8% comorbidity)
2. Autoimmune Thyroid disease (3%)
3. Dermatitis Herpetiformis
4. Sjogren's Syndrome
5. Primary Biliary Cirrhosis
6. Addison's Disease
7. Systemic Lupus Erythematosus
8. Selective IgA Deficiency (2-8%)
9. Alopecia Areata
10. Autoimmune Hepatitis
11. Sarcoidosis
12. Vitiligo
13. Psoriasis

Symptoms (secondary to malabsorption)

Many cases are asymptomatic
1. Subclinical presentation in 10% of children and 21% of adults (as high as 38% in some studies)
Diarrhea (up to 85%)
1. Represents 5% of Chronic Diarrhea patients
2. Chronic Fatty Diarrhea in most cases
3. May also cause Osmotic Diarrhea from Bile Acid Malabsorption
Fatigue (80%)
Weight loss (45%)
Abdominal Distention (33%)
Excessive Flatus or Eructation (28%)
Large, bulky, foul smelling stools
Other associated symptoms
1. Aphthous Stomatitis
2. Constipation
3. Gastroesophageal Reflux Disease

Signs
Age-related Presentations

Gastrointestinal symptoms as described below
Infants and toddlers
1. Classic onset ages 6-24 months with Diarrhea, Abdominal Pain, Abdominal Distention and Vomiting
2. Failure to Thrive
3. Short Stature
4. Developmental Delay
5. Malnutrition
Older children
1. Constitutional Short Stature
2. Delayed Puberty
3. Dental enamel defect
4. Epilepsy
Adults
1. Osteopenia or Osteoporosis
2. Anemia
3. Transaminitis
4. Recurrent Miscarriage
5. Lactose Intolerance
  1. Transient until mucosal lesions (related to immunologic injury) heal

Signs
General

Anemia (50% of cases)
1. Occult blood loss from Small Bowel inflammation
2. Malabsorption
  1. Iron Deficiency Anemia (most common)
  2. Vitamin B12 Deficiency
  3. Folate Deficiency
Other Vitamin malabsorption (especially fat soluble Vitamins A, D, E , K as well as B Vitamins)
1. Osteoporosis (Vitamin D Deficiency)
2. Coagulopathy (Vitamin K Deficiency)
Dermatitis Herpetiformis (10-20% of cases)
1. Pathognomonic extraintestinal manifestation of Celiac Disease

Diagnosis
Serologic Testing

Indications for testing
1. Celiac Disease in first or second degree relatives
2. Thyroid disease
3. Type I Diabetes Mellitus
4. Down Syndrome or Turner's Syndrome
5. Infertility
Other Indications for testing
1. Irritable Bowel Syndrome
2. Iron Deficiency Anemia
3. Chronic Diarrhea
4. Chronic Fatigue
5. Unintentional Weight Loss
6. Short Stature
7. Osteoporosis
8. Liver Function Test abnormalities (AST or ALT)
Precautions
1. Avoid empiric Gluten-Free Diet without testing
  1. Differential diagnosis is broad and may improve on Gluten-Free Diet (e.g. Irritable Bowel Syndrome)
  2. Positive Predictive Value of Gluten-Free Diet for Celiac Disease diagnosis: 36%
2. False Negative testing risks
  1. Serology may be less accurate in age under 5 years (and especially under age 2 years)
  2. Serology and biopsy may be falsely negative if patient on Gluten-Free Diet
    1. Especially if on restriction >6-12 months
    2. Consider testing after eating gluten containing diet for at least 2 to 6 weeks OR
    3. Consider HLA Genetic Testing for Class II DQ2 and DQ8 (excludes Celiac Disease if negative)
Antibody testing
1. Anti-tissue transglutaminase Antibody (TTG)
  1. Most sensitive test for Celiac Sprue
  2. Test Sensitivity: 95-98% (as low as 63 to 93% in some studies)
  3. Test Specificity: 94-95%
2. IgA anti-endomysial Antibody (EMA)
  1. Test Sensitivity: >90%
  2. Test Specificity: >95%
  3. False Negative in IgA deficient and age under 3 years
  4. May be used to confirm a positive TTG
3. IgG Deaminated gliadin peptide
  1. Test Sensitivity: >80%
  2. Test Specificity: >98%
4. Anti-gliadin antibodies (not recommended, low sensitivity)
  1. IgA anti-gliadin Antibody
    1. Test Sensitivity: >53
    2. Test Specificity: >65
  2. IgG anti-gliadin Antibody
    1. Test Sensitivity: >57
    2. Test Specificity: >42
Protocol
1. Initial labs (obtain both)
  1. Total IgA
    1. Identifies IgA deficiency found in 2-3% (>10 fold increased Prevalence in Celiac Disease)
    2. Identifies cases where IgG Gliadin should be used in place of IgA TTG
  2. IgA Tissue Transglutaminase (TTG)
    1. Obtain IgG deaminated gliadin peptide (in place of TTG) if IgA deficiency
    2. IgA anti-endomysial Antibody (EMA) may be used to confirm positive TTG in children
      1. However endoscopic biopsy is recommended in adults for confirmation
2. Interpretation: IgA TTG (or IgG deaminated gliadin peptide if IgA deficiency)
  1. Tests negative : Celiac Sprue is unlikely
    1. Test Sensitivity is dependent on mucosal inflammation
    2. Risk of False Negative tests in subclinical disease and in IgA deficiency
    3. Consider Small Bowel biopsy if high suspicion remains
    4. HLA Genetic Testing for Class II DQ2 and DQ8 negative rules out Celiac Disease
  2. Tests positive: Highly suggestive of Celiac Sprue (esp. titers >10x normal)
    1. Correlates with extensive villous atrophy
    2. Confirm with Small Bowel biopsy (due to False Positives)
  3. Alternatives to Small Bowel biopsy for Celiac Sprue diagnosis
    1. IgA TTG levels >10x normal in infants and children OR
    2. Skin biopsy consistent with Dermatitis Herpetiformis

Diagnosis
Endoscopy with Small Bowel biopsy

Indications
1. IgA deficiency (Serology unreliable)
2. Confirmation of Celiac Sprue diagnosis (esp. adults) after positive Serology
3. High level of suspicion yet negative Serologic Testing
Endoscopic biopsy of distal duodenum (gold standard)
1. Villous atrophy with reactive crypt hyperplasia
2. Four tissue samples are recommended to reduce False Negative Rate

Differential Diagnosis

Anorexia Nervosa
Inflammatory Bowel Disease (e.g. Crohn's Disease)
Intestinal infection (e.g. Giardiasis, Clostridium difficile, Tropical Sprue)
Malabsorption (e.g. Lactose Intolerance)
Mesenteric Ischemia
Tuberculosis
Intestinal Lymphoma
Immunodeficiency (e.g. Human Immunodeficiency Virus, Hypogammaglobulinemia)
Whipple's Disease
Zollinger-Ellison Syndrome
Medication-induced (e.g. Olmesartan or Benicar)
Irritable Bowel Syndrome
1. Initial misdiagnosis in 36% of patients ultimately diagnosed with Celiac Disease

Labs
Initial at Time of Initial Diagnosis

Complete Blood Count with Platelets
Iron studies (Serum Iron, TIBC, Ferritin)
Serum Vitamin B12
Serum Folate
Serum Calcium
Serum Vitamin D
Serum Phosphorus
Renal Function tests (Blood Urea Nitrogen, Creatinine)
Liver Function Tests (AST, ALT, Albumin, Alk Phos)
1. Increased transaminase levels (AST, ALT) in 20-40% of cases at the time of diagnosis
Consider micronutrient testing (zinc level, copper level)

Imaging (at time of diagnosis and as warranted)

DEXA Scan of spine and hips
1. Osteopenia in one third of patients at diagnosis
2. Osteoporosis in one third of patients at diagnosis

Management

See Gluten-Free Diet
Strict Gluten-Free Diet (life long)
1. Consider registered dietician Consultation
2. Dietary gluten threshold to allow for healing: <10 to 50 mg gluten/day
  1. For perspective, a single slice of wheat bread contains 2 grams of gluten (200 fold over limit)
  2. Patients should plan meals, and Exercise caution in purchase of pre-prepared food and dining out
  3. Cross contamination with gluten is common
3. Symptom relief achieved in 70 to 93% of patients within 6-12 months of Gluten-Free Diet
  1. Diarrhea improves in first 60 days in 80% of patients on Gluten-Free Diet
4. Gluten-Free Diet non-compliance is the most common cause of refractory symptoms (35 to 50% of cases)
  1. Consider registered dietician referral
5. Up to 5% of patients are refractory to strict dietary restriction and may need Immunosuppressant therapy
  1. Refer refractory patients to gastroenterology for further management
  2. Consider comorbid conditions
    1. Lactose Intolerance
    2. Bacterial overgrowth
    3. Irritable Bowel Syndrome
    4. Microscopic Colitis
Consider monitoring with serologic markers (e.g. IgA TTG as described above)
1. Serologic Markers should return to normal within 3-12 months of starting Gluten-Free Diet
2. Persistent positive markers suggests continued gluten exposure (although Serology is inconsistent)
3. Transition to negative Serology is associated with mucosal healing
Monitoring
1. Close interval follow-up in first year after diagnosis, and then every 1 to 2 years
2. Follow growth curves (weight, height) in children
3. Consider repeat lab testing (see initial labs above, e.g. CBC, B12, Iron) at follow-up if previously abnormal
4. Review symptoms and Gluten-Free Diet compliance

Complications

Osteoporosis (from Calcium and Vitamin D malabsorption)
Neurologic disorders
1. Cerebral calcifications
2. Ataxia
3. Peripheral Neuropathy
4. Seizure Disorder
Untreated or refractory Celiac Sprue complications
1. Intestinal stricture (and Bowel Obstruction)
2. Non-Hodgkin's Lymphoma (Relative Risk: 3 to 6)
3. Small intestinal cancers (Relative Risk: 10)
  1. T-Cell Lymphoma
  2. Cryptic Lymphoma should be considered if refractory
4. Oropharyngeal cancers (Relative Risk: 2.3)
5. Esophageal Cancers (Relative Risk: 4.2)
6. Right-sided bowel adenocarcinoma (Relative Risk: 2.3)
7. Primary liver cancer (Relative Risk: 2.7)
8. Vitamin Deficiency
  1. Iron Deficiency
  2. Vitamin B12 Deficiency
  3. Vitamin C Deficiency
  4. Folate Deficiency
  5. Calcium Deficiency, Vitamin D Deficiency and Osteoporosis (increased Hip Fracture risk)
  6. Selenium Deficiency
  7. Zinc Deficiency
  8. Hypomagnesemia

Course
Following gluten free diet started

Clinical improvement in several days
Restoration of normal histology in weeks to months
Diarrhea recurrence despite Gluten-Free Diet causes
1. Gluten returned to diet (most common)
2. Lactose Intolerance
3. Microscopic Colitis
4. Pancreatic insufficiency
5. Irritable Bowel Syndrome
6. Refractory Celiac Sprue
7. Small intestinal cancer (T-Cell Lymphoma)

Resources

Celiac Sprue Association
1. http://www.csaceliacs.org
2. PO Box 31700 Omaha, Nebraska 68131,Tel: 402/558-0600
Celiac Disease and Gluten-Free Diet Support Page
1. http://www.celiac.com
Celiac Disease Foundation
1. http://www.celiac.org
Celiac Disease resources for providers
1. http://www.uams.edu/celiac

References