II. 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%)
- 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
- Monozygotic twins: 75% concordance rate
- First degree relatives: 10% have Celiac Disease
- Second degree relatives: 3-6% have Celiac Disease
III. Pathophysiology
- Small Bowel exposure to Antigens in cereal grains (rye, wheat, barley)
- Immunologic disorder of Small Bowel
- Related to HLA Class II DQA1*0501 and DQB1*0201 (HLA-DQ2 and HLA-DQ8)
- Associated with other Autoimmune Conditions as below
- Absence of both HLA-DQ2 and HLA-DQ8 makes the diagnosis of Celiac Sprue highly unlikely
- However these haplotypes are present in more the 25% of the general population
- Only 4% of patients with HLA-DQ2 or HLA-DQ8 develop Celiac Sprue
IV. Risk Factors: Adults
- See Associated Conditions below
- See epidemiologic factors and above
-
Family History
- See HLA-DQ2 and HLA-DQ8 genetic association as above
- First degree relatives (esp. monozygous twins): 10% affected
- Second degree relatives: 3 to 6% affected
V. Risk Factors: Children
- See Associated Conditions below (includes chromosomal abnormalities)
- Risk factors
- Ceserean delivery
- Rotavirus infection
- Gluten exposure before age 5 years
- Previously thought that gluten exposure ages 3 to 7 months was protective
- Later studies show increased risk if exposed under age 5 years and no protective effect window
- Protective factors
- Breast Feeding (disproven)
- Longer duration of Breast Feeding including the time of first gluten exposure was thought protective
- Later studies do not demonstrate Breast Feeding protection against Celiac Disease
- Breast Feeding (disproven)
- References
VI. Associated Conditions
- Chromosomal abnormality
- Turner's Syndrome (6%)
- Down Syndrome (8%)
- Williams Syndrome (8%)
-
Autoimmune Conditions
- Type I Diabetes Mellitus (2-8% comorbidity)
- Autoimmune Thyroid disease (3%)
- Dermatitis Herpetiformis
- Sjogren's Syndrome
- Primary biliary Cirrhosis
- Addison's Disease
- Systemic Lupus Erythematosus
- Selective IgA Deficiency (2-8%)
- Alopecia Areata
- Autoimmune Hepatitis
- Sarcoidosis
- Vitiligo
- Psoriasis
VII. Symptoms (secondary to malabsorption)
- Many cases are asymptomatic
- Subclinical presentation in 10% of children and 21% of adults (as high as 38% in some studies)
-
Diarrhea (up to 85%)
- Represents 5% of Chronic Diarrhea patients
- Chronic Fatty Diarrhea in most cases
- 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
VIII. Signs: Age-related Presentations
- Gastrointestinal symptoms as described below
- Infants and toddlers
- Classic onset ages 6-24 months with Diarrhea, Abdominal Pain, Abdominal Distention and Vomiting
- Failure to Thrive
- Short Stature
- Developmental Delay
- Malnutrition
- Older children
- Constitutional Short Stature
- Delayed Puberty
- Dental enamel defect
- Epilepsy
- Adults
- Osteopenia or Osteoporosis
- Anemia
- Transaminitis
- Recurrent Miscarriage
- Lactose Intolerance
- Transient until mucosal lesions (related to immunologic injury) heal
IX. Signs: General
-
Anemia (50% of cases)
- Occult blood loss from Small Bowel inflammation
- Malabsorption
- Other Vitamin malabsorption (especially fat soluble Vitamins A, D, E , K as well as B Vitamins)
-
Dermatitis Herpetiformis (10-20% of cases)
- Pathognomonic extraintestinal manifestation of Celiac Disease
X. Diagnosis: Serologic Testing
- Indications for testing
- Celiac Disease in first or second degree relatives
- Thyroid disease
- Type I Diabetes Mellitus
- Down Syndrome or Turner's Syndrome
- Infertility
- Other Indications for testing
- Irritable Bowel Syndrome
- Iron Deficiency Anemia
- Chronic Diarrhea
- Chronic Fatigue
- Unintentional Weight Loss
- Short Stature
- Osteoporosis
- Liver Function Test abnormalities (AST or ALT)
- Precautions
- Avoid empiric Gluten-Free Diet without testing
- Differential diagnosis is broad and may improve on Gluten-Free Diet (e.g. Irritable Bowel Syndrome)
- Positive Predictive Value of Gluten-Free Diet for Celiac Disease diagnosis: 36%
- False Negative testing risks
- Serology may be less accurate in age under 5 years (and especially under age 2 years)
- Serology and biopsy may be falsely negative if patient on Gluten-Free Diet
- Especially if on restriction >6-12 months
- Consider testing after eating gluten containing diet for at least 2 to 6 weeks OR
- Consider HLA Genetic Testing for Class II DQ2 and DQ8 (excludes Celiac Disease if negative)
- Avoid empiric Gluten-Free Diet without testing
-
Antibody testing
- Anti-tissue transglutaminase Antibody (TTG)
- Most sensitive test for Celiac Sprue
- Test Sensitivity: 95-98% (as low as 63 to 93% in some studies)
- Test Specificity: 94-95%
- IgA anti-endomysial Antibody (EMA)
- Test Sensitivity: >90%
- Test Specificity: >95%
- False Negative in IgA deficient and age under 3 years
- May be used to confirm a positive TTG
- IgG Deaminated gliadin peptide
- Test Sensitivity: >80%
- Test Specificity: >98%
- Anti-gliadin antibodies (not recommended, low sensitivity)
- IgA anti-gliadin Antibody
- Test Sensitivity: >53
- Test Specificity: >65
- IgG anti-gliadin Antibody
- Test Sensitivity: >57
- Test Specificity: >42
- IgA anti-gliadin Antibody
- Anti-tissue transglutaminase Antibody (TTG)
- Protocol
- Initial labs (obtain both)
- Total IgA
- Identifies IgA deficiency found in 2-3% (>10 fold increased Prevalence in Celiac Disease)
- Identifies cases where IgG Gliadin should be used in place of IgA TTG
- IgA Tissue Transglutaminase (TTG)
- Obtain IgG deaminated gliadin peptide (in place of TTG) if IgA deficiency
- IgA anti-endomysial Antibody (EMA) may be used to confirm positive TTG in children
- However endoscopic biopsy is recommended in adults for confirmation
- Total IgA
- Interpretation: IgA TTG (or IgG deaminated gliadin peptide if IgA deficiency)
- Tests negative : Celiac Sprue is unlikely
- Test Sensitivity is dependent on mucosal inflammation
- Risk of False Negative tests in subclinical disease and in IgA deficiency
- Consider Small Bowel biopsy if high suspicion remains
- HLA Genetic Testing for Class II DQ2 and DQ8 negative rules out Celiac Disease
- Tests positive: Highly suggestive of Celiac Sprue (esp. titers >10x normal)
- Correlates with extensive villous atrophy
- Confirm with Small Bowel biopsy (due to False Positives)
- Alternatives to Small Bowel biopsy for Celiac Sprue diagnosis
- IgA TTG levels >10x normal in infants and children OR
- Skin biopsy consistent with Dermatitis Herpetiformis
- Tests negative : Celiac Sprue is unlikely
- Initial labs (obtain both)
XI. Diagnosis: Endoscopy with Small Bowel biopsy
- Indications
- IgA deficiency (Serology unreliable)
- Confirmation of Celiac Sprue diagnosis (esp. adults) after positive Serology
- High level of suspicion yet negative Serologic Testing
- Endoscopic biopsy of distal duodenum (gold standard)
- Villous atrophy with reactive crypt hyperplasia
- Four tissue samples are recommended to reduce False Negative Rate
XII. 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
- Initial misdiagnosis in 36% of patients ultimately diagnosed with Celiac Disease
XIII. 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)
- Increased transaminase levels (AST, ALT) in 20-40% of cases at the time of diagnosis
- Consider micronutrient testing (zinc level, copper level)
XIV. Imaging (at time of diagnosis and as warranted)
-
DEXA Scan of spine and hips
- Osteopenia in one third of patients at diagnosis
- Osteoporosis in one third of patients at diagnosis
XV. Management
- See Gluten-Free Diet
- Strict Gluten-Free Diet (life long)
- Consider registered dietician Consultation
- Dietary gluten threshold to allow for healing: <10 to 50 mg gluten/day
- For perspective, a single slice of wheat bread contains 2 grams of gluten (200 fold over limit)
- Patients should plan meals, and Exercise caution in purchase of pre-prepared food and dining out
- Cross contamination with gluten is common
- Symptom relief achieved in 70 to 93% of patients within 6-12 months of Gluten-Free Diet
- Diarrhea improves in first 60 days in 80% of patients on Gluten-Free Diet
- Gluten-Free Diet non-compliance is the most common cause of refractory symptoms (35 to 50% of cases)
- Consider registered dietician referral
- Up to 5% of patients are refractory to strict dietary restriction and may need Immunosuppressant therapy
- Refer refractory patients to gastroenterology for further management
- Consider comorbid conditions
- Consider monitoring with serologic markers (e.g. IgA TTG as described above)
- Serologic Markers should return to normal within 3-12 months of starting Gluten-Free Diet
- Persistent positive markers suggests continued gluten exposure (although Serology is inconsistent)
- Transition to negative Serology is associated with mucosal healing
- Monitoring
- Close interval follow-up in first year after diagnosis, and then every 1 to 2 years
- Follow growth curves (weight, height) in children
- Consider repeat lab testing (see initial labs above, e.g. CBC, B12, Iron) at follow-up if previously abnormal
- Review symptoms and Gluten-Free Diet compliance
XVI. Complications
- Osteoporosis (from Calcium and Vitamin D malabsorption)
- Neurologic disorders
- Cerebral calcifications
- Ataxia
- Peripheral Neuropathy
- Seizure Disorder
- Untreated or refractory Celiac Sprue complications
- Intestinal stricture (and Bowel Obstruction)
- Non-Hodgkin's Lymphoma (Relative Risk: 3 to 6)
- Small intestinal cancers (Relative Risk: 10)
- T-Cell Lymphoma
- Cryptic Lymphoma should be considered if refractory
- Oropharyngeal cancers (Relative Risk: 2.3)
- Esophageal Cancers (Relative Risk: 4.2)
- Right-sided bowel adenocarcinoma (Relative Risk: 2.3)
- Primary liver cancer (Relative Risk: 2.7)
- Vitamin Deficiency
- Iron Deficiency
- Vitamin B12 Deficiency
- Vitamin C Deficiency
- Folate Deficiency
- Calcium Deficiency, Vitamin D Deficiency and Osteoporosis (increased Hip Fracture risk)
- Selenium Deficiency
- Zinc Deficiency
- Hypomagnesemia
XVII. 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
- Gluten returned to diet (most common)
- Lactose Intolerance
- Microscopic Colitis
- Pancreatic insufficiency
- Irritable Bowel Syndrome
- Refractory Celiac Sprue
- Small intestinal cancer (T-Cell Lymphoma)
XVIII. Resources
- Celiac Sprue Association
- http://www.csaceliacs.org
- PO Box 31700 Omaha, Nebraska 68131,Tel: 402/558-0600
- Celiac Disease and Gluten-Free Diet Support Page
- Celiac Disease Foundation
- Celiac Disease resources for providers
XIX. References
- Ciclitira (2001) Gastroenterology 120:1526-40 [PubMed]
- Dewar (2005) Gastroenterology 128: S19-S24 [PubMed]
- Farrell (2002) N Engl J Med 346:180-8 [PubMed]
- Green (2007) N Engl J Med 357(17): 1731-43 [PubMed]
- Lewis (2006) Aliment Pharmacol Ther 24:47-54 [PubMed]
- Nelsen (2002) Am Fam Physician 66(12):2259-66 [PubMed]
- Pelkowski (2014) Am Fam Physician 89(2): 99-105 [PubMed]
- Presutti (2007) Am Fam Physician 76(12): 1795-1810 [PubMed]
- Rubio-Tapia (2023) Am J Gastroenterol 118(1): 59-76 [PubMed]
- Treem (2004) Curr Opin Pediatr 16:552-559 [PubMed]
- Volta (2014) BMC Gastroenterol 14:194 [PubMed]
- Williams (2022) Am Fam Physician 106(1): 36-43 [PubMed]