Gluten Enteropathy

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

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II. 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%)
    1. Prevalence 2 to 4% in those with chronic abdominal symptoms
  5. More common in white patients and 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

III. 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

IV. Risk Factors: Adults

  1. See Associated Conditions below
  2. See epidemiologic factors and above
  3. 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

V. Risk Factors: Children

  1. See Associated Conditions below (includes chromosomal abnormalities)
  2. 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
  3. 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
  4. References
    1. Aronsson (2019) JAMA 322(6): 514-23 [PubMed]
    2. Vriezinga (2014) N Engl J Med 371(14): 1304-15 [PubMed]
    3. Lionetti (2014) N Engl J Med 371(14): 1295-303 [PubMed]

VI. 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. 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

VII. Symptoms (secondary to malabsorption)

  1. Many cases are asymptomatic
    1. Subclinical presentation in 10% of children and 21% of adults (as high as 38% in some studies)
  2. 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
  3. Fatigue (80%)
  4. Weight loss (45%)
  5. Abdominal Distention (33%)
  6. Excessive Flatus or Eructation (28%)
  7. Large, bulky, foul smelling stools
  8. Other associated symptoms
    1. Aphthous Stomatitis
    2. Constipation
    3. Gastroesophageal Reflux Disease

VIII. 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
    3. Short Stature
    4. Developmental Delay
    5. Malnutrition
  3. Older children
    1. Constitutional Short Stature
    2. Delayed Puberty
    3. Dental enamel defect
    4. Epilepsy
  4. 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

IX. Signs: General

  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

X. 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
        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)
  4. 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
  5. 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

XI. Diagnosis: Endoscopy with Small Bowel biopsy

  1. 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
  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

XII. 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

XIII. 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. Serum Calcium
  6. Serum Vitamin D
  7. Serum Phosphorus
  8. Renal Function tests (Blood Urea Nitrogen, Creatinine)
  9. Liver Function Tests (AST, ALT, Albumin, Alk Phos)
    1. Increased transaminase levels (AST, ALT) in 20-40% of cases at the time of diagnosis
  10. Consider micronutrient testing (zinc level, copper level)

XIV. 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

XV. Management

  1. See Gluten-Free Diet
  2. 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
  3. 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
  4. 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

XVI. 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)
    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

XVII. 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)

XVIII. 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

XIX. References

  1. Ciclitira (2001) Gastroenterology 120:1526-40 [PubMed]
  2. Dewar (2005) Gastroenterology 128: S19-S24 [PubMed]
  3. Farrell (2002) N Engl J Med 346:180-8 [PubMed]
  4. Green (2007) N Engl J Med 357(17): 1731-43 [PubMed]
  5. Lewis (2006) Aliment Pharmacol Ther 24:47-54 [PubMed]
  6. Nelsen (2002) Am Fam Physician 66(12):2259-66 [PubMed]
  7. Pelkowski (2014) Am Fam Physician 89(2): 99-105 [PubMed]
  8. Presutti (2007) Am Fam Physician 76(12): 1795-1810 [PubMed]
  9. Rubio-Tapia (2023) Am J Gastroenterol 118(1): 59-76 [PubMed]
  10. Treem (2004) Curr Opin Pediatr 16:552-559 [PubMed]
  11. Volta (2014) BMC Gastroenterol 14:194 [PubMed]
  12. Williams (2022) Am Fam Physician 106(1): 36-43 [PubMed]

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