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%)
  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

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
  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 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
    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
  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
      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

Images: Related links to external sites (from Bing)

Related Studies

Ontology: Celiac Disease (C0007570)

Definition (MSH) A malabsorption syndrome that is precipitated by the ingestion of foods containing GLUTEN, such as wheat, rye, and barley. It is characterized by INFLAMMATION of the SMALL INTESTINE, loss of MICROVILLI structure, failed INTESTINAL ABSORPTION, and MALNUTRITION.
Definition (MEDLINEPLUS)

Celiac disease is an immune disease in which people can't eat gluten because it will damage their small intestine. If you have celiac disease and eat foods with gluten, your immune system responds by damaging the small intestine. Gluten is a protein found in wheat, rye, and barley. It is found mainly in foods but may also be in other products like medicines, vitamins and supplements, lip balm, and even the glue on stamps and envelopes.

Celiac disease affects each person differently. Symptoms may occur in the digestive system, or in other parts of the body. One person might have diarrhea and abdominal pain, while another person may be irritable or depressed. Irritability is one of the most common symptoms in children. Some people have no symptoms.

Celiac disease is genetic. Blood tests can help your doctor diagnose the disease. Your doctor may also need to examine a small piece of tissue from your small intestine. Treatment is a diet free of gluten.

NIH: National Institute of Diabetes and Digestive and Kidney Diseases

Definition (NCI_NCI-GLOSS) A digestive disease that is caused by an immune response to a protein called gluten, which is found in wheat, rye, barley, and oats. Celiac disease damages the lining of the small intestine and interferes with the absorption of nutrients from food. A person with celiac disease may become malnourished no matter how much food is consumed.
Definition (NCI) An autoimmune genetic disorder with an unknown pattern of inheritance that primarily affects the digestive tract. It is caused by intolerance to dietary gluten. Consumption of gluten protein triggers an immune response which damages small intestinal villi and prevents adequate absorption of nutrients. Clinical signs include abdominal cramping, diarrhea or constipation and weight loss. If untreated, the clinical course may progress to malnutrition, anemia, osteoporosis and an increased risk of intestinal malignancies. However, the prognosis is favorable with successful avoidance of gluten in the diet.
Definition (CSP) disease occurring in children and adults characterized by sensitivity to gluten, with chronic inflammation and atrophy of the mucosa of the upper small intestine; manifestations include diarrhea, malabsorption, steatorrhea, and nutritional and vitamin deficiencies.
Concepts Disease or Syndrome (T047)
MSH D002446
ICD9 579.0
ICD10 K90.0
SnomedCT 266478000, 155842007, 197481005, 23829007, 197477005, 396331005
LNC LA15156-5
English Celiac Disease, Enteropathies, Gluten, Gluten Enteropathies, Gluten Enteropathy, Disease, Celiac, Enteropathy, Gluten, Celiac disease NOS, Coeliac disease NOS, GSE - Gluten-sens enteropathy, Gluten-induced enteropathy, Gluten-induced enteropathy syn, Gluten-Induced Enteropathy, Non Tropical Sprue, CELIAC DISEASE, CD, CELIAC SPRUE, GLUTEN-SENSITIVE ENTEROPATHY, GSE, CELIAC DIS, celiac sprue, idiopathic steatorrhea, celiac idiopathic steatorrhea (diagnosis), gluten enteropathy, celiac idiopathic steatorrhea, gluten enteropathy (diagnosis), nontropical sprue, celiac disease (diagnosis), celiac disease, Gluten sensitive enteropathy, Gluten intolerance, Celiac Disease [Disease/Finding], gluten-induced enteropathy, non tropical sprue, celiac diseases, sprue, Disease;coeliac, Intolerance;gluten, non-tropical sprue, celiac syndrome, coeliac syndrome, celiac sprues, gluten-sensitive enteropathy, sprues, Celiac Sprue, Gluten Intolerance, Nontropical Sprue, Sprue, Coeliac disease (disorder), Sprue - nontropical, Celiac disease NOS (disorder), Steatorrhoea - idiopathic, Steatorrhea - idiopathic, Enteropathy, Gluten-Sensitive, Gluten Sensitive Enteropathy, Gluten-Sensitive Enteropathies, Sprue, Celiac, Sprue, Nontropical, Gluten-Sensitive Enteropathy, Enteropathies, Gluten-Sensitive, Gluten-induced enteropathy syndrome, Non-tropical sprue, Celiac disease, Celiac sprue, Gluten enteropathy, Idiopathic steatorrhea, Nontropical sprue, Wheat-sensitive enteropathy, Celiac syndrome, Coeliac disease, Coeliac sprue, Coeliac syndrome, GSE - Gluten-sensitive enteropathy, Gluten-responsive sprue, Gluten-sensitive enteropathy, Idiopathic steatorrhoea, CS - Celiac sprue, CS - Coeliac sprue, CD - Celiac disease, CD - Coeliac disease, Celiac disease (disorder), celiac, Thaysen, enteropathy; gluten-sensitive, gluten-sensitive; enteropathy, idiopathic; steatorrhea, nontropical; sprue, sprue; nontropical, steatorrhea; idiopathic, Coeliac disease [Ambiguous], coeliac disease, Disease;celiac, gluten intolerance
Dutch niet-tropische spruw, glutengevoelige enteropathie, glutenenteropathie, glutenintolerantie, enteropathie; glutensensitief, glutensensitief; enteropathie, idiopathisch; steatorroe, niet-tropisch; spruw, spruw; niet-tropisch, steatorroe; idiopathisch, coeliakie, Coeliakie, Gluten-enteropathie, Spruw, glutengevoelige, Spruw, niet-tropische
French Entéropathie par sensibilité au gluten, Intolérance au gluten, Sprue non tropicale, Maladie céliaque, Maladie coeliaque, Entéropathie au gluten, Entéropathie chronique liée à une intolérance au gluten, Maladie de Gee, Sprue coeliaque, Sprue nostras, Sprue, Syndrome caeliaque par intolérance au gluten
German glutenempfindliche Enteropathie, Glutenunvertraeglichkeit, nichttropischer Sprue, einheimische Sprue, Zoeliakie, Enteropathie, Gluten-sensitive, Gluten-sensitive Enteropathie, Glutenenteropathie, Zöliakie
Italian Intolleranza al glutine, Malattia celiaca, Enteropatia da glutine, Celiachia, Sprue non tropicale, Enteropatia glutine-sensibile, Sprue celiaca, Morbo celiaco
Portuguese Espru celíaco, Enteropatia de intolerância ao glúten, Intolerância ao glúten, Espru não tropical, Estearreia, Doença celíaca, Doença Celíaca, Enteropatia Glúten Induzida, Espru Celíaco, Espru não Tropical
Spanish Enteropatía por gluten, Esprue no tropical, Sprue celiaco, Esprue celiaco, Intolerancia al gluten, Enteropatía sensible al gluten, Coeliac disease [Ambiguous], enfermedad celíaca, SAI (trastorno), enteropatía por gluten, enfermedad celíaca, SAI, esprue celíaco, crisis celíaca, enteropatía sensible a los cereales, esprue no tropical, esteatorrea idiopática, Coeliac disease, celíaco de esprue, enfermedad celíaca (trastorno), enfermedad celíaca, Enfermedad celiaca, Enfermedad Celíaca, Enteropatía por Gluten, Esprue Celíaco, Esprue no Tropical
Japanese グルテン不耐症, 非熱帯性スプルー, グルテン過敏性腸症, グルテンフタイショウ, セリアックスプルー, グルテンチョウショウ, ヒネッタイセイスプルー, セリアックビョウ, グルテンカビンセイチョウショウ, セリアック病, グルテン腸症, グルテン性腸症, 小児脂肪便症, ツェリアキー, スプルー, ツエリアキー, Celiac病, セリアックスプルー, 幼稚症性脂肪便症
Swedish Glutenintolerans
Czech sprue celiakální, celiakie, gluténová enteropatie, Celiakie, Glutenová enteropatie, Celiakální sprue, Non-tropická sprue, Intolerance glutenu, Gluten senzitivní enteropatie, celiakální sprue, gluten-senzitivní enteropatie
Finnish Keliakia
Korean 복강질환
Polish Celiakia, Sprue, Biegunka tłuszczowa dziecięca, Choroba trzewna, Upośledzone wchłanianie glutenu
Hungarian Coeliakia, Gluten enteropathia, Nem trópusi sprue, Coeliaca betegség, Gluten intolerantia, Gluten sensitiv enteropathia
Norwegian Cøliaki, Glutenindusert enteropati, Ikke-tropisk sprue