Malabsorption

Gluten Enteropathy

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Gluten Enteropathy, Gluten Sensitive Enteropathy, Celiac Sprue, Celiac Disease, Coeliac Disease, Nontropical Sprue, Gluten-Induced Enteropathy

  • Epidemiology
  1. Affects both adults and children
  2. May present as Failure to Thrive in infants
  3. Older patients over age 60 years represent 20% of cases
  4. Prevalence: 1 per 120-300 in United States and Europe (0.5 to 1%)
  5. Rare in asian patients
  6. More common in women (75% of adult cases)
  7. 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
  1. Small Bowel exposure to antigens in cereal grains (rye, wheat, barley)
  2. 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
  3. 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
  • Children
  1. No known risk factors in adults (beyond epidemiologic factors and associated conditions)
  2. Risk factors
    1. Ceserean delivery
    2. Rotavirus infection
  3. Protective factors
    1. Breast Feeding
      1. Longer duration of Breast Feeding including the time of first gluten exposure
    2. Gluten exposure between 3 and 7 months of age
      1. Increased risk if gluten introduced before 3 months or after 7 months
  • Associated conditions
  1. Chromosomal abnormality
    1. Turner's Syndrome (6%)
    2. Down Syndrome (8%)
    3. Williams Syndrome (8%)
  2. Autoimmune Conditions
    1. Type I Diabetes Mellitus (2-8% comorbidity)
    2. Autoimmune Thyroid disease (3%)
    3. Sjogren's Syndrome
    4. Primary biliary Cirrhosis
    5. Addison's Disease
    6. Systemic Lupus Erythematosus
    7. Selective IgA Deficiency (2-8%)
    8. Alopecia Areata
    9. Autoimmune Hepatitis
    10. Sarcoidosis
    11. Vitiligo
    12. Psoriasis
  • Symptoms (secondary to malabsorption)
  1. Many cases are asymptomatic (up to 38%)
  2. Diarrhea (up to 85%)
  3. Fatigue (80%)
  4. Weight loss (45%)
  5. Abdominal Distention (33%)
  6. Excessive Flatus or Eructation (28%)
  7. Large, bulky, foul smelling stools
  • Signs
  • Age-related Presentations
  1. Gastrointestinal symptoms as described below
  2. Infants and toddlers
    1. Classic onset ages 6-24 months with Diarrhea, Abdominal Pain, Abdominal Distention and Vomiting
    2. Failure to Thrive or Short Stature
    3. Developmental Delay
    4. Malnutrition
  3. Older children
    1. Constitutional Short Stature
    2. Dental enamel defect
    3. Epilepsy
  4. Adults
    1. Osteopenia or Osteoporosis
    2. Anemia
    3. Lactose Intolerance
      1. Transient until mucosal lesions (related to immunologic injury) heal
  1. 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
  2. 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)
  3. Dermatitis Herpetiformis (10-20% of cases)
    1. Pathognomonic extraintestinal manifestation of Celiac Disease
  • Diagnosis
  • Serologic testing
  1. 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
  2. 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)
  3. 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
  4. Antibody testing
    1. Anti-tissue transglutaminase Antibody (TTG)
      1. Most sensitive test for Celiac Sprue
      2. Test Sensitivity: 95-98%
      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, 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
  5. Protocol
    1. Initial labs (obtain both)
      1. Total IgA
        1. Identifies IgA deficiency (>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. Previously, IgA anti-endomysial Antibody (EMA) was used to confirm positive TTG (now, biopsy instead)
    2. Interpretation: IgA TTG (or IgG deaminated gliadin peptide)
      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
      2. Tests positive: Highly suggestive of Celiac Sprue
        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
  1. Indications
    1. IgA deficiency (serology unreliable)
    2. Confirmation of Celiac Sprue diagnosis
    3. High level of suspicion yet negative serologic testing
  2. 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
  1. Anorexia Nervosa
  2. Inflammatory Bowel Disease (e.g. Crohn's Disease)
  3. Intestinal infection (e.g. Giardiasis, Clostridium difficile, Tropical Sprue)
  4. Malabsorption (e.g. Lactose Intolerance)
  5. Mesenteric Ischemia
  6. Tuberculosis
  7. Intestinal Lymphoma
  8. Immunodeficiency (e.g. Human Immunodeficiency Virus, Hypogammaglobulinemia)
  9. Whipple's Disease
  10. Zollinger-Ellison Syndrome
  11. Medication-induced (e.g. Olmesartan or Benicar)
  12. Irritable Bowel Syndrome
    1. Initial misdiagnosis in 36% of patients ultimately diagnosed with Celiac Disease
  • Labs
  • Initial at time of initial diagnosis
  1. Complete Blood Count with platelets
  2. Iron studies (Serum Iron, TIBC, Ferritin)
  3. Serum Vitamin B12
  4. Serum Folate
  5. Calcium
  6. Phosphate
  7. Renal Function tests (Blood Urea Nitrogen, Creatinine)
  8. Liver Function Tests (AST, ALT, Albumin, Alk Phos)
    1. Increased transaminase levels (AST, ALT) in 20-40% of cases at the time of diagnosis
  • Imaging (at time of diagnosis and as warranted)
  1. 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
  1. Strict Gluten-Free Diet
    1. Dietary gluten threshold to allow for healing: <50 mg gluten/day
    2. Up to 5% of patients are refractory to strict dietary restriction and may need immunosuppressant therapy
  2. Consider monitoring with serologic markers (e.g. IgA TTG as described above)
    1. Should return to normal within 3-12 months of starting Gluten-Free Diet
    2. Persistent positive markers suggests continued gluten exposure
  • Complications
  1. Osteoporosis (from calcium and Vitamin D malabsorption)
  2. Neurologic disorders
    1. Cerebral calcifications
    2. Ataxia
    3. Peripheral Neuropathy
    4. Seizure disorder
  3. 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)
  • Course
  • Following gluten free diet started
  1. Clinical improvement in several days
  2. Restoration of normal histology in weeks to months
  3. 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
  1. Celiac Sprue Association
    1. http://www.csaceliacs.org
    2. PO Box 31700 Omaha, Nebraska 68131,Tel: 402/558-0600
  2. Celiac Disease and Gluten-Free Diet Support Page
    1. http://www.celiac.com
  3. Celiac Disease Foundation
    1. http://www.celiac.org
  4. Celiac Disease resources for providers
    1. http://www.uams.edu/celiac