Celiac Disease (Sprue)
- Author: Stephan U Goebel, MD; Chief Editor: BS Anand, MD more...
Celiac disease, also known as celiac sprue or gluten-sensitive enteropathy, is a chronic disorder of the digestive tract that results in an inability to tolerate gliadin, the alcohol-soluble fraction of gluten. Gluten is a protein commonly found in wheat, rye, and barley.
When patients with celiac disease ingest gliadin, an immunologically mediated inflammatory response occurs that damages the mucosa of their intestines, resulting in maldigestion and malabsorption of food nutrients.
Signs and symptoms
Diarrhea - 45-85% of patients
Flatulence - 28% of patients
Borborygmus - 35-72% of patients
Weight loss - 45% of patients; in infants and young children with untreated celiac disease, failure to thrive and growth retardation are common
Weakness and fatigue - 78-80% of patients; usually related to general poor nutrition
Severe abdominal pain - 34-64% of patients
Anemia - 10-15% of patients
Osteopenia and osteoporosis - 1-34% of patients
Neurologic symptoms - 8-14% of patients; include motor weakness, paresthesias with sensory loss, and ataxia; seizures may develop 
Skin disorders - 10-20% of patients; including dermatitis herpetiformis, a condition with pruritic, papulovesicular skin lesions involving the extensor surfaces of the extremities, trunk, buttocks, scalp, and neck
Hormonal disorders - Including amenorrhea, delayed menarche, and infertility in women and impotence and infertility in men
A bleeding diathesis is usually caused by prothrombin deficiency, due to impaired absorption of fat-soluble vitamin K.
A physical exam may reveal the following:
A protuberant and tympanic abdomen
Evidence of weight loss
Hyperkeratosis or dermatitis herpetiformis
Cheilosis and glossitis
Evidence of peripheral neuropathy
Chvostek or Trousseau sign (seen in calcium deficiency)
See Clinical Presentation for more detail.
The American College of Gastroenterology (ACG) recommends that antibody testing, especially immunoglobulin A anti-tissue transglutaminase antibody (IgA TTG), is the best first test for suspected celiac disease, although biopsies are needed for confirmation; in children younger than 2 years, the IgA TTG test should be combined with testing for IgG-deamidated gliadin peptides.[2, 3]
Other laboratory tests include the following:
Electrolytes and chemistries - Electrolyte imbalances; evidence of malnutrition
Hematologic tests - Anemia, low serum iron level, prolonged prothrombin time (PT)
Stool examination - Fat malabsorption
Oral tolerance tests - Lactose intolerance
Serology - Immunoglobulin A (IgA) antibodies
Patients diagnosed with celiac disease should be examined for deficiencies, including low bone density. Patients already on a gluten-free diet without prior testing need to be evaluated to assess the likelihood that celiac disease is present; genetic testing and a gluten challenge are most helpful.[2, 3]
Radiographic evaluation of the small bowel after barium ingestion is helpful in making a diagnosis of untreated celiac disease. Abnormal radiographic findings can include dilatation of the small intestine, a coarsening or obliteration of the normally delicate mucosal pattern, and fragmentation or flocculation of the barium in the gut lumen.
Endoscopy and biopsy
Upper endoscopy with at least 6 duodenal biopsies is considered the criterion standard to help establish a diagnosis of celiac disease. Histologically, duodenal biopsies can be graded into the following 5 stages:
Stage 0 - Normal
Stage 1 - Increased percentage of intraepithelial lymphocytes (>30%)
Stage 2 - Increased presence of inflammatory cells and crypt cell proliferation with preserved villous architecture
Stage 3 - Mild (A), moderate (B), and subtotal to total (C) villous atrophy
Stage 4 - Total mucosal hypoplasia
See Workup for more detail.
The primary treatment of celiac disease is dietary. Removal of gluten from the diet is essential, although complete avoidance of gluten-containing grain products is relatively difficult for patients to achieve and maintain; certain products, such as wheat flour, are virtually ubiquitous in the American diet.
A small percentage of patients with celiac disease fail to respond to a gluten-free diet. In some patients who are refractory, corticosteroids may be helpful.
Celiac disease, also known as celiac disease or gluten-sensitive enteropathy, is a chronic disease of the digestive tract that interferes with the digestion and absorption of food nutrients. People with celiac disease cannot tolerate gliadin, the alcohol-soluble fraction of gluten. Gluten is a protein commonly found in wheat, rye, and barley. Most patients with celiac disease tolerate oats, but they should be monitored closely. When people with celiac disease ingest gliadin, the mucosa of their intestines is damaged by an immunologically mediated inflammatory response, resulting in maldigestion and malabsorption. Patients with celiac disease can present with failure to thrive and diarrhea (the classical form). However, some patients have only subtle symptoms (atypical celiac disease) or are asymptomatic (silent celiac disease).
Celiac disease has a strong hereditary component. The prevalence of the condition in first-degree relatives is approximately 10%.
A strong association exists between celiac disease and two human leukocyte antigen (HLA) haplotypes (DQ2 and DQ8). Damage to the intestinal mucosa is seen with the presentation of gluten-derived peptide gliadin, consisting of 33 amino acids, by the HLA molecules to helper T cells. Helper T cells mediate the inflammatory response. Endogenous tissue transglutaminase deamidates gliadin into a negatively charged protein, increasing its immunogenicity. Absence of intestinal villi and lengthening of intestinal crypts characterize the mucosal lesions in untreated celiac disease. More lymphocytes infiltrate the epithelium (intraepithelial lymphocytes). Destruction of the absorptive surface of the intestine leads to a maldigestive and malabsorption syndrome.
Celiac disease results from a combination of immunological responses to an environmental factor (gliadin) and genetic factors.[6, 7]
The interaction of alcohol-soluble gliadin in wheat, barley, and rye products with the mucosa of the small intestine is crucial to the pathogenesis of celiac disease. Endogenous tissue transglutaminase deamidates glutamine in gliadin, converting it from a neutral to a negatively charged protein. Negatively charged gliadin has been shown to induce interleukin 15 in enteric epithelial cells, stimulating the proliferation of natural killer cells and intraepithelial lymphocytes to express NK-G2D, a marker for natural killer T lymphocytes.
Gliadin (a complex mixture of proline- and glutamine-rich polypeptides obtained by alcohol extraction of wheat gluten) can produce symptoms and histological changes in the small intestine when administered to patients with asymptomatic celiac disease. Antigliadin antibodies can frequently be identified in untreated patients.
Immunoglobulin A (IgA) antibodies to smooth muscle endomysium and tissue transglutaminase (the most commonly used test) are used for serological diagnosis. However, 3-5% of all patients with celiac disease are IgA deficient. Therefore, determining total IgA prior to antibody testing is appropriate in patients with celiac disease.
Cell-mediated immune responses are also important for the pathogenesis of celiac disease, as demonstrated by the presence of large numbers of CD8+ T lymphocytes in the intestinal epithelium.
Genetics play an important role in celiac disease. The incidence of celiac disease in relatives of patients with celiac disease is significantly higher than in the general population. The prevalence in first-degree relatives of patients with celiac disease is approximately 10%. Concordance for the disease in monozygotic twins approaches 75% and is approximately 30% for first-degree relatives.
Gliadin binds to HLA-DQ2 heterodimers or HLA-DQ8 heterodimers found in 90-95% and 5-10% of patients with celiac disease, respectively. HLA-DQ2 and HLA-DQ8 are present on the surface of antigen-presenting cells in the lamina propria, and binding of gliadin leads to expression of the proinflammatory cytokine interferon gamma and activation of CD4+ T lymphocytes.
United States statistics
The frequency of celiac disease in the United States is relatively low, about 1 case in 3000 persons. Estimates suggest that approximately 1% of the Western population is affected, but celiac disease is underdiagnosed in most affected people.[6, 7]
Because the historical prevalence and long-term outcome of undiagnosed celiac disease were unknown, Rubio-Tapia et al collected serologic information on 3 cohorts : 9,133 healthy young adults from whom sera were collected between 1948 and 1954, and 12,768 gender-matched subjects from 2 recent cohorts, one whose years of birth were similar to those of members of the first cohort, and the other whose age at sampling was similar.
The sera were first tested for tissue transglutaminase, then, if abnormal, for endomysial antibodies. During 45 years of follow-up in the older cohort, all-cause mortality was nearly 4-fold greater in persons with undiagnosed celiac disease than among those who were seronegative (hazard ratio = 3.9; 95% confidence interval, 2.0-7.5; P <0.001). Comparison of the older and more recent cohorts suggested that undiagnosed celiac disease in the United States has increased dramatically in the past half century: 0.2% of the older cohort had undiagnosed celiac disease compared with 0.8% of the cohort with similar years of birth and 0.9% of those with similar age at sampling (P ≤0.0001).
Approximately 3 million people in Europe and another 3 million people in the United States are estimated to be affected by celiac disease. Celiac disease is prevalent in European countries with temperate climates. The highest prevalence of celiac disease is in Ireland and Finland and in places to which Europeans emigrated, notably North America and Australia. In these populations, celiac disease affects approximately 1 in 100 individuals. The incidence of celiac disease is increasing among certain populations in Africa (Saharawui population), Asia (India),[10, 11] and the Middle East.
Race-. sex-, and age-related demongraphics
Celiac disease is most prevalent in Western Europe and the United States, with an increasing incidence in Africa and Asia. Females are affected slightly more than males.
The age distribution of patients with celiac disease is bimodal, the first at 8-12 months and the second in the third to fourth decades. The mean age at diagnosis is 8.4 years (range, 1-17 y).
Celiac disease might become apparent in infants when gluten ingestion begins. Symptoms of celiac disease might persist throughout childhood if untreated but usually diminish in adolescence. Symptoms often reappear in early adulthood, between the third and fourth decades of life.
Approximately 20% of patients with celiac disease are older than 60 years.
Adolescents with celiac disease frequently present with extraintestinal manifestations, including short stature, behavioral problems, fatigue, and skin problems. The diagnosis of celiac disease is often not established until middle age or old age.
The prognosis for patients with correctly diagnosed and treated celiac disease is excellent.
The prognosis for patients with celiac disease who are not responding to gluten withdrawal and corticosteroid treatment is generally poor.
Although rarely lethal, celiac disease is a significant and often debilitating maldigestive and malabsorption syndrome affecting multiple organ systems.
Patients with celia disease are at an increased risk for complications, such as lymphomas and adenocarcinomas of the intestinal tract.
Untreated pregnant women are at risk of miscarriage and at risk of having a baby with a congenital malformation.
Short stature often results when celiac disease prevents nutrient absorption during the childhood years when nutrition is critical to growth and development.
Symptoms of celiac disease malabsorption can include one or more of the following (see History):
Abdominal bloating or cramps
The risk for malignant disease is increased in patients with celiac disease. These malignancies include adenocarcinoma of the oropharynx, esophagus, pancreas, small and large bowel, and hepatobiliary tract. Other malignancies with an increased incidence in patients with celiac disease are enteropathy-associated T-cell lymphoma with a poor prognosis and T- and B-cell non-Hodgkin lymphoma.
A study in Sweden reported increased cataract risk (hazard ratio = 1.28) in patients with celiac disease compared with age-matched and sex-matched controls.
Refractory celiac disease occurs in approximately 5% of patients despite strict adherence to a gliadin-free diet. Refractory celiac disease is characterized by symptoms of malabsorption, weight loss, diarrhea, abdominal distention, and anemia.
Refractory celiac disease is subdivided into two types: Type 1 is characterized by a normal intraepithelial lymphocyte phenotype, and type 2 is characterized with an increased number of intraepithelial lymphocytes, possibly due to an increase in epithelial interleukin 15 expression.
Ludvigsson JF, Zingone F, Tomson T, Ekbom A, Ciacci C. Increased risk of epilepsy in biopsy-verified celiac disease: A population-based cohort study. Neurology. 2012 May 1. 78(18):1401-7. [Medline].
Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA. ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease. Am J Gastroenterol. 2013 May. 108(5):656-76. [Medline].
Douglas D. ACG Issues Celiac Disease Guidelines. Medscape. May 3 2013. Available at http://www.medscape.com/viewarticle/803586. Accessed: May 15 2013.
Green PH, Cellier C. Celiac disease. N Engl J Med. 2007 Oct 25. 357(17):1731-43. [Medline].
Kagnoff MF. Celiac disease: pathogenesis of a model immunogenetic disease. J Clin Invest. 2007 Jan. 117(1):41-9. [Medline].
Green PH, Lebwohl B, Greywoode R. Celiac disease. J Allergy Clin Immunol. 2015 May. 135 (5):1099-106; quiz 1107. [Medline].
Kelly CP, Bai JC, Liu E, Leffler DA. Advances in diagnosis and management of celiac disease. Gastroenterology. 2015 May. 148 (6):1175-86. [Medline].
Tursi A, Brandimarte G, Giorgetti GM. Prevalence of antitissue transglutaminase antibodies in different degrees of intestinal damage in celiac disease. J Clin Gastroenterol. 2003 Mar. 36(3):219-21. [Medline].
Yachha SK, Misra S, Malik AK, Nagi B, Mehta S. Spectrum of malabsorption syndrome in north Indian children. Indian J Gastroenterol. 1993 Oct. 12(4):120-5. [Medline].
Cummins AG, Roberts-Thomson IC. Prevalence of celiac disease in the Asia-Pacific region. J Gastroenterol Hepatol. 2009 Aug. 24(8):1347-51. [Medline].
Rashtak S, Murray JA. Celiac disease in the elderly. Gastroenterol Clin North Am. 2009 Sep. 38(3):433-46. [Medline].
Mollazadegan K, Kugelberg M, Lindblad BE, Ludvigsson JF. Increased risk of cataract among 28,000 patients with celiac disease. Am J Epidemiol. 2011 Jul 15. 174(2):195-202. [Medline].
Lowry F. Current screening guidelines fail to identify celiac disease. Medscape Medical News. January 13, 2014. [Full Text].
Boggs W. Genetic testing might improve diagnosis of celiac disease. Medscape Medical News. September 10, 2013. [Full Text].
Anderson RP, Henry MJ, Taylor R, Duncan EL, Danoy P, Costa MJ, et al. A novel serogenetic approach determines the community prevalence of celiac disease and informs improved diagnostic pathways. BMC Med. 2013 Aug 28. 11(1):188. [Medline]. [Full Text].
Errichiello S, Esposito O, Di Mase R, Camarca ME, Natale C, Limongelli MG, et al. Celiac Disease: Predictors of Compliance With a Gluten-free Diet in Adolescents and Young Adults. J Pediatr Gastroenterol Nutr. 2009 Jul 28. [Medline].
Abutaleb Y. FDA issues new rules for labeling 'gluten-free' foods. Reuters Health Information. August 02, 2013. [Full Text].
US Food and Drug Administration. FDA defines "gluten-free" for food labeling [press release]. August 2, 2013. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm363474.htm. Accessed: August 12, 2013.
Vriezinga SL, Auricchio R, Bravi E, et al. Randomized feeding intervention in infants at high risk for celiac disease. N Engl J Med. 2014 Oct 2. 371(14):1304-15. [Medline].
Lionetti E, Castellaneta S, Francavilla R, et al. Introduction of gluten, HLA status, and the risk of celiac disease in children. N Engl J Med. 2014 Oct 2. 371(14):1295-303. [Medline].
Askling J, Linet M, Gridley G, et al. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology. 2002 Nov. 123(5):1428-35. [Medline].
Catassi C, Rätsch IM, Fabiani E, Rossini M, Bordicchia F, Candela F. Coeliac disease in the year 2000: exploring the iceberg. Lancet. 1994 Jan 22. 343(8891):200-3. [Medline].
Collin P, Kaukinen K, Vogelsang H, et al. Antiendomysial and antihuman recombinant tissue transglutaminase antibodies in the diagnosis of coeliac disease: a biopsy-proven European multicentre study. Eur J Gastroenterol Hepatol. 2005 Jan. 17(1):85-91. [Medline].
Cristofori F, Fontana C, Magistà A, Capriati T, Indrio F, Castellaneta S, et al. Increased Prevalence of Celiac Disease Among Pediatric Patients With Irritable Bowel Syndrome: A 6-Year Prospective Cohort Study. JAMA Pediatr. 2014 Apr 21. [Medline].
Dieterich W, Ehnis T, Bauer M, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med. 1997 Jul. 3(7):797-801. [Medline].
Farrell RJ, Kelly CP. Celiac sprue. N Engl J Med. 2002 Jan 17. 346(3):180-8. [Medline].
Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multicenter study. Arch Intern Med. 2003 Feb 10. 163(3):286-92. [Medline].
Ferguson A, Arranz E, O'Mahony S. Clinical and pathological spectrum of coeliac disease--active, silent, latent, potential. Gut. 1993 Feb. 34(2):150-1. [Medline].
Frellick M. Celiac Disease Screening Should Focus on Kids With IBS. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/823915. Accessed: April 27, 2014.
Godkin A, Jewell D. The pathogenesis of celiac disease. Gastroenterology. 1998 Jul. 115(1):206-10. [Medline].
Greco L, Romino R, Coto I, et al. The first large population based twin study of coeliac disease. Gut. 2002 May. 50(5):624-8. [Medline].
Green PH, Jabri B. Coeliac disease. Lancet. 2003 Aug 2. 362(9381):383-91. [Medline].
Harding A. Endoscopy without biopsy may miss many with celiac disease. Reuters Health Information. March 17, 2014. [Full Text].
James MW, Scott BB. Coeliac disease: the cause of the various associated disorders?. Eur J Gastroenterol Hepatol. 2001 Sep. 13(9):1119-21. [Medline].
Johnson TC, Diamond B, Memeo L, et al. Relationship of HLA-DQ8 and severity of celiac disease: comparison of New York and Parisian cohorts. Clin Gastroenterol Hepatol. 2004 Oct. 2(10):888-94. [Medline].
Lewis R. Pediatric Celiac Disease More Common With HLA Haplotype. Medscape Medical News. Available at http://www.medscape.com/viewarticle/827791. Accessed: July 6, 2014.
Liu E, Lee HS, Aronsson CA, Hagopian WA, Koletzko S, Rewers MJ, et al. Risk of pediatric celiac disease according to HLA haplotype and country. N Engl J Med. 2014 Jul 3. 371(1):42-9. [Medline].
Mention JJ, Ben Ahmed M, Begue B, et al. Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology. 2003 Sep. 125(3):730-45. [Medline].
Murray JA, Van Dyke C, Plevak MF, et al. Trends in the identification and clinical features of celiac disease in a North American community, 1950-2001. Clin Gastroenterol Hepatol. 2003 Jan. 1(1):19-27. [Medline].
Pietzak MM, Schofield TC, McGinniss MJ, Nakamura RM. Stratifying risk for celiac disease in a large at-risk United States population by using HLA alleles. Clin Gastroenterol Hepatol. 2009 Sep. 7(9):966-71. [Medline].
Rashtak S, Murray JA. Celiac disease in the elderly. Gastroenterol Clin North Am. 2009 Sep. 38(3):433-46. [Medline].
Rostami K, Malekzadeh R, Shahbazkhani B, et al. Coeliac disease in Middle Eastern countries: a challenge for the evolutionary history of this complex disorder?. Dig Liver Dis. 2004 Oct. 36(10):694-7. [Medline].
Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology. 2006 Dec. 131(6):1981-2002. [Medline].
Salmi TT, Collin P, Korponay-Szabo IR, et al. Endomysial antibody-negative coeliac disease: clinical characteristics and intestinal autoantibody deposits. Gut. 2006 Dec. 55(12):1746-53. [Medline].
Sanders DS, Hurlstone DP, McAlindon ME, et al. Antibody negative coeliac disease presenting in elderly people--an easily missed diagnosis. BMJ. 2005 Apr 2. 330(7494):775-6. [Medline].
Sategna-Guidetti C, Pulitanó R, Grosso S, et al. Serum IgA antiendomysium antibody titers as a marker of intestinal involvement and diet compliance in adult celiac sprue. J Clin Gastroenterol. 1993 Sep. 17(2):123-7. [Medline].
Smedby KE, Akerman M, Hildebrand H, et al. Malignant lymphomas in coeliac disease: evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma. Gut. 2005 Jan. 54(1):54-9. [Medline].
Squires JE, Fei L, Cohen MB. Role of Celiac Disease Screening for Children With Functional Gastrointestinal Disorders. JAMA Pediatr. 2014 Apr 21. [Medline].