Celiac Disease and
Celiac disease (CD) is a chronic immune-mediated disorder that develops in genetically susceptible persons when gluten, a major protein found in wheat, barley, and rye is ingested in the diet. Also called non-tropical sprue, or gluten-sensitive enteropathy, CD is primarily an enteropathy characterized by inflammation of the small bowel mucosa and atrophy of the villi, resulting in nutrient malabsorption, wasting, and diarrhea. These symptoms define the classical or typical symptoms of CD.
Any organ system may be involved in CD, and patients can develop extra-intestinal manifestations defined as non-classical symptomatic CD and include anemia, bone disease, infertility, unfavorable outcomes of pregnancy, lymphoma, and liver disease. The term sub-clinical CD defines patients who have signs of CD, iron deficiency anemia for example, but no symptoms. Potential CD is preferable over latent CD and it relates to people with a normal small intestinal mucosa who are at increased risk of developing CD as indicated by CD serology. Non-celiac gluten sensitivity (NCGS) occurs with ingestion of gluten in patients in whom CD has been excluded by serology and small bowel biopsy and should be differentiated from CD.
Genetic susceptibility defines people who possess the gene pair encoding the major histocompatibility complex class II HLA DQ2 or DQ8. These genes are virtually required for CD to occur, and lack of these genes makes CD very unlikely.
Prevalence and Epidemiology
Availability of novel serologic tests that are highly sensitive and specific such as endomysial and human tissue transglutaminase antibodies (EMA and hTTG) has made it possible to assess the true prevalence of CD. Epidemiologic studies using such tests along with small bowel biopsies report a higher prevalence of CD than previously thought. Prevalence in Western Europeans and in the United States is reported to range between 1 in 250 to 1 in 133, and it is higher in relatives of persons with CD, occurring in 1 in 22 first-degree relatives and in 1 in 39 second-degree relatives. It is rarely, if ever, reported in people with pure ethnic backgrounds from Africa, the Caribbean, China, and Japan. Women are affected more commonly than men, but there is no age predilection.
Other than people who have relatives with CD, people at increased risk include those with Down syndrome, Turner syndrome, type 1 diabetes mellitus, thyroid disease, lymphocytic colitis, and autoimmune disorders (Table 1).
|Table 1. Patients Who Are at Risk for Celiac Disease and Should Be Tested for the Disease|
|Patients with gastrointestinal and classical symptoms: diarrhea, weight loss, abdominal distention, failure to thrive|
|Patients with autoimmune diseases, type 1 diabetes, thyroid disorders, Sjögren’s syndrome, microscopic colitis, inflammatory bowel disease|
|First-degree relatives of affected people|
|Patients with elevated liver enzymes|
|Patients with Down syndrome|
|Patients with Williams syndrome|
|Patients with iron deficiency anemia|
|Patients with osteoporosis|
|Patients with delayed puberty|
|Patients with irritable bowel syndrome|
Celiac disease is a multifactorial and a multisystem disorder involving a genetic predisposition, environmental exposure of the small bowel mucosa to gluten, and an immunologic response to gluten.
The majority (>90%) of people with CD possess the HLA DQ2 haplotype, and 5% to 10% possess the DQ8 haplotype, conferring a negative predictive value greater than 98%. These haplotypes are encoded within the HLA class II region of the major histocompatibility complex on chromosome 6p. However, about 40% of the general population carry these haplotypes without having the disease, which makes their presence necessary but not sufficient for its development. Other non-HLA genes have been proposed, but their role in influencing the disease has not been clearly defined.
It was a serendipitous observation that children with CD improved during World War II when cereals used to make bread were scarce, and they relapsed after the war when the supply of these cereals was reinstituted. Risk for developing CD is increased with the introduction of gluten in the diet of infants before the age of 4 months. Grains that activate the disease contain proteins that can form gluten (prolamins: glutenins and gliadins) and include wheat, barley, and rye. Grains that do not activate the disease include rice, corn, sorghum, and millet. Oats contain a very small proportion of prolamins and should be avoided initially.
Exposure of the upper small bowel mucosa to gluten in susceptible people precipitates an immune mediated reaction that involves both the innate and the adaptive immune responses. Tissue trans-glutaminase, an enzyme present in the lamina propria of the small bowel, deamidates glutamine residues in gluten to form glutamic acid. Glutamic acid is a negatively charged molecule that is recognized by the antigen-precipitating cells that express the HLA DQ2/DQ8 receptors for T lymphocytes. T lymphocytes become activated and they begin to divide rapidly and secrete several immunomodulators such as immunoglobulins, cytokines, interferons, tumor necrosis factor, and interleukin 15 and 17 that cause damage to the enterocytes and result in villous atrophy.
Celiac disease exhibits a spectrum of clinical and pathologic manifestations. Left untreated, CD can progress to involve multiple organ systems with severe complications and nutritional deficiencies.
Symptoms can manifest in infancy and as early as cereals are introduced in the diet. Crampy abdominal pain, steatorrhea, failure to thrive, apathy and irritability, muscle wasting, and hypotonia are described. Any of these symptoms should trigger a diagnostic workup. Catch-up growth is well documented once a gluten- free diet is introduced.
In adults, the clinical symptoms are variable and not specific. The classical symptoms of malabsorption are less and less encountered since testing with serological antibodies has become available, and extra-intestinal symptoms are increasingly recognized before the full-blown clinical wasting occurs. Patients can exhibit weakness, fatigue, and dyspnea as a result of vitamin B12, folate, and iron deficiency; bone fractures, muscular atrophy, and tetany as a result of osteoporosis and osteopenia due to vitamin D and calcium deficiencies; peripheral neuropathy and ataxia as a result of cerebellar and posterior column inflammatory damage; and secondary hyperparathyroidism, edema, petechiae, and dermatitis herpetiformis. Infertility is observed in men and women. Amenorrhea, intrauterine growth retardation, and unfavorable outcomes of pregnancy have been reported. Liver enzyme abnormalities and nonspecific hepatitis have been incidentally recognized in patients with CD, and advanced liver disease and cirrhosis have been reported, with improvement of the liver disease upon withdrawal of gluten from the diet. It is generally accepted that patients with abnormal elevation of liver enzymes should be tested for celiac disease.
Dermatitis herpetiformis is a cutaneous manifestation of small intestinal immune-mediated enteropathy that is precipitated by exposure to dietary gluten. It is characterized by IgA deposits in the dermo-epidermal junction and an intensely pruritic papulovesicular rash that affects the buttocks and the extensor surfaces of elbows and knees. Most patients have abnormalities of the intestinal mucosa. Treatment consists of withdrawing gluten from the diet. If skin lesions do not improve, dapsone may be added at 1 to 2 mg/day.
Other manifestations of CD include weight gain and obesity, gastroesophageal reflux disease, irritable bowel syndrome with abdominal pain and constipation, pancreatitis, myocarditis, aphthous ulcers of the oral mucosa, lymphocytic and collagenous colitis, hyposplenism, and asymptomatic IgA nephropathy. There is a slightly higher risk for gastrointestinal malignancies and lymphomas in CD patients than in the general population.
Once the clinical suspicion in patients at risk factors is raised, the initial step toward a diagnosis is to test for celiac serology antibody . This should be followed by a small bowel biopsy. The patient should be tested while following a gluten-containing diet.
The most sensitive and specific serologic tests are endomysial antibody IgA EMA and human tissue transglutaminase antibody IgA (hTTG). Sensitivities and specificities are higher than 85% and 97% respectively for EMA ,and 90% and 97% respectively for hTTG. In children, antibody levels above 10 times normal may be used to diagnose CD without a biopsy. Gliadin antibodies have lower sensitivities and specificities and are not recommended for diagnosis.
About 2% to 5% of patients with CD have selective IgA deficiency, in which case serum IgG hTTG or IgG EMA testing should be performed.
Pathologic changes on small-bowel biopsy are characterized by a spectrum of abnormalities described by Marsh and known as the Marsh criteria (Table 2). The hallmark of CD is Marsh 3 or villous atrophy; however, this may be patchy or present in other disorders as in hypogammaglobulinemia, acute infectious gastroenteritis, lymphoma, Crohn disease, or milk intolerance.
Table 2. Histologic Spectrum of Intestinal Involvement in Celiac Disease
|Marsh 0 or type 0||Pre-infiltrative or normal|
|Marsh I or type 1||Infiltrative lesion; increased intraepithelial lymphocytes|
|Marsh II or type 2||Hyperplastic lesion (type 1 plus crypt hyperplasia)|
|Marsh III or type 3||Destructive lesion (type 2 plus villous atrophy)|
|Marsh IV or type 4||Hypoplastic lesion seen in T cell lymphoma|
Establishing Diagnosis in the Absence of Typical Symptoms
The wide range of clinical manifestations of the disease coupled with less than Marsh 3 on biopsy makes the diagnosis of CD challenging for the clinician. In these situations, genetic testing or gluten challenge may be necessary for a definite diagnosis. A few scenarios may be encountered in a clinical setting and their proposed diagnostic workups include:
- Positive serology and villous atrophy: Diagnosis established. Patient should be treated.
- Positive serology and normal small bowel mucosa biopsy or increased intraepithelial lymphocytes: Latent or potential CD. Biopsy should be repeated after a gluten challenge or a few months later on a normal diet. Consider HLA typing. If any is positive, start a gluten-free diet and monitor response.
- Normal serology and normal biopsy: Look for other causes of the patient's symptoms.
- Normal serology and villous atrophy: Exclude other causes of villous atrophy or IgA deficiency.
Gluten challenge should be performed in patients who embarked on a gluten-free diet empirically without serologic or pathologic abnormalities. It can also be done in patients with latent or potential celiac disease. Gluten should be started in small increments beginning with one slice of bread and doubling this amount every 3 days if tolerated until at least 10 g of gluten are ingested daily or the equivalent of 4 slices of bread. Serologic testing and small bowel biopsy should be repeated and signs and symptoms observed. If tests remain negative, patients should remain on a normal diet.
Mass screening for CD in the general population is not recommended. This is due to the large heterogeneity of the clinical presentation and the unclear outcome in asymptomatic patients. Screening with EMA and hTTG may be warranted in patients at risk (Table 1).
- Refractory celiac disease consists of persistent symptoms and villous atrophy despite a strict gluten free diet for more than 12 months. Glucocorticoids and at times immunosuppressants are indicated to induce remission. Patients often progress to ulcerative jejunitis or malignancy.
- Malignancy related to CD includes enteropathy-associated intestinal lymphoma or enteropathy-associated T-cell lymphoma and various carcinomas along the gastrointestinal tract. These are not responsive to a gluten-free diet.
- Ulcerative jejunoileitis consists of ulcers and strictures of the small bowel, requiring surgical resections.
- Acute celiac crisis is rare and usually occurs when patients undergo rapid and non-incremental gluten challenge. It is characterized by severe diarrhea, electrolyte abnormalities, and metabolic acidosis. Glucocorticoids and volume replacement are often required.
- Collagenous sprue defines CD that is refractory to therapy and characterized by the deposition of collagen in subepithelial regions of the small bowel with a thickness greater than 10 mm. Prognosis for collagenous sprue is very grim.
Treatment of CD consists of withdrawing gluten from the diet for life. It entails eliminating wheat, barley, and rye. This allows healing of the small bowel mucosa and restitution of normal nutritional status. Oats may initially be withdrawn in severely symptomatic patients until symptoms begin to resolve.
Lactose-containing products can worsen gastrointestinal symptoms and should be avoided initially until restitution of a normal mucosa. Deficiencies of vitamins D and B12, folic acid, calcium, and iron and other nutritional deficiencies should be replaced as necessary. Prevention of bone loss and pneumococcal vaccination due to hyposplenism are necessary. Complications of CD should be managed appropriately, and increased vigilance in recognizing and managing lymphomas and cancers is very important in these patients.
Adherence to a gluten-free diet is often difficult because of cost and lack of palatability and because it requires the patient's commitment and perseverance. Therefore, alternative therapies are increasingly in demand, and trials are ongoing to assess for their efficacy. These therapies include gluten-degrading enzymes, modified grains that lack immunogenic compounds, zonulin inhibitors that decrease intestinal permeability, and anti-inflammatory and immunotherapy.
Referral of patients to nutritional counseling for education and for monitoring adherence and response to therapy is essential to safeguard and good outcome. Information on gluten-containing and gluten-free foods is available on various websites along with a wide variety of gluten-free recipes.
Response to the gluten-free diet is assessed by clinical and serologic improvement. There is no clear consensus on whether a repeat small bowel biopsy is necessary. However, repeat biopsy may be indicated in cases where adherence to diet is proved but response to diet is equivocal or lacking.
Other malabsorption disorders
The small intestine is the site of absorption of nutrients necessary to maintain life. The integrity of both the intestinal mucosa and the intestinal chyme (luminal) are necessary for absorption to occur. Several disorders that affect nutrient absorption are grouped into these 2 categories (Table 3) and should be included in the differential diagnosis of CD.
Table 3. Differential Diagnosis of Celiac Disease
|Tropical sprue||Mucosal||Nonspecific enterotoxigens||Acute enteric infection in visitors of endemic locales||Antibiotics|
|Whipple disease||Mucosal||Tropheryma whippelli||Small bowel biopsy, PAS+ laden macrophages||Antibiotics|
|Disaccharidase deficiency (lactose intolerance)||Mucosal||Lactase deficiency of villous epithelial cells||Hydrogen breath test||Avoidance of milk products|
|Abetalipoproteinemia||Luminal||Autosomal recessive inability to synthesize abetalipoproteins||Absence in plasma of chylomicrons, VLDLs, and LDLs Burr cells on blood smear||Avoidance of milk products|
|Crohn's disease||Mucosal||Autoimmune disorder of the GI tract||Clinical, endoscopic and histological||5 ASA and immunosuppressants|
|Eosinophilic gastroenteritis, mastocytosis||Mucosal||Inflammation||Histologic||Steroids|
|Gastrectomy, ileal resection and short gut syndrome||Mucosal and luminal||Surgical, iatrogenic||Clinical history, B12 deficiency, other deficiencies||B12 supplementation, nutritional supplementation|
|Graft versus host disease||Mucosal||Iatrogenic||Clinical history||Withdrawal of offending agents|
|AIDS||Mucosal||Infectious agents, AIDS enteropathy||Possibly histologic||Antibiotics, antiretroviral therapy|
|Pancreatic insufficiency||Luminal||Chronic pancreatitis, cystic fibrosis||Clinical radiological and laboratory||Pancreatic enzymes|
|Zollinger-Ellison||Luminal||Gastrinoma||Clinical radiological and laboratory||Resection|
|Bacterial overgrowth||Luminal||Breath tests, small bowel cultures||Antibiotics|
|Drugs: bile acid binders, antacids, methotrexate, sulfasalazine||Luminal||Decrease micelle formation, chelation, villus blunting, inhibition of folate hydrolase||Withdrawal of the precipitating agents|
ASA, acetylsalicylic acid; GI, gastrointestinal; LDL, low-density lipoprotein; PAS, periodic acid-Schiff; VLDL, very-low-density lipoprotein.
CD is a an immune-mediated enteropathy and a multisystem disorder with a wide range of clinical presentations. Clinicians should have a heightened awareness of these presentations and a low threshold for testing with EMA and hTTG antibodies. Education and surveillance of patients on a gluten-free diet are crucial to safeguard adherence to the diet and prevent further complications of the disease.
Other malabsorptive disorders should be included in the differential diagnosis of CD, bearing in mind the similarities in signs and symptoms and the pathologic findings on biopsy. Further testing may be required, and a multidisciplinary approach may be necessary for a definite diagnosis.
- Celiac disease is an immune-mediated disorder that develops in genetically susceptible persons when gluten is ingested in the diet. Exposure of the upper small bowel mucosa to gluten precipitates an inflammatory reaction characterized by infiltration of the lamina propria and the epithelium with inflammatory cells, which eventually leads to destruction and atrophy of the mucosa.
- Prevalence in Western Europe and in the United States ranges between 1 in 250 and 1 in 133. It is higher in relatives of people with celiac disease. Women are affected more commonly than men, but there is no age predilection.
- Diarrhea and fat malabsorption are the classical symptoms of CD. However, patients may present with extraintestinal manifestation of deficiencies caused by prolonged malabsorption, including anemia, bone disease, infertility, unfavorable outcomes of pregnancy, lymphoma, and liver disease.
- The diagnosis should be suspected in any patient with chronic diarrhea, and in those with unexplained deficiency states including iron, folate, and fat-soluble vitamins. The most sensitive and specific serologic tests are endomysial antibody IgA EMA and tissue transglutaminase antibody IgA hTTG. Biopsy of the small intestine plays a confirmatory role.
- Treatment consists of withdrawing gluten from the diet for life. It entails eliminating wheat, barley, and rye.
- Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for coeliac disease and related terms. Gut. 2012 Feb 16. [Epub ahead of print] PMID: 22345659
- AGA Institute: AGA Institute medical position statement on the diagnosis and management of celiac disease. Gastroenterology 2006;131(6);1977-2002.
- Husby S, Koletzko S, Korponay-Szabó IR, et al.; ESPGHAN Working Group on Coeliac Disease Diagnosis; ESPGHAN Gastroenterology Committee; European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54(1):136-60.
- Kaukinen K, Collin P, Mäki M: Latent celiac disease or celiac disease beyond villous atrophy? Gut 2007;56(10):1339-1340.
- Kurppa K, Collin P, Viljamaa M, et al: Diagnosing mild enteropathy celiac disease: A randomized, controlled clinical study. Gastroenterology 2009;136(3):816-823.
- Marsh MN: Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (“celiac sprue”). Gastroenterology 1992;102(1):330- 354.
- NIH Consensus Development Conference on Celiac Disease. NIH Consens State Sci Statements. 2004;21(1):1-23.
- Qiao SW, Sollid LM, Blumberg RS: Antigen presentation in celiac disease. Curr Opin Immunol 2009;21(1):111-117.
- Sollid LM, Markussen G, Ek J, et al: Evidence of a primary association of celiac disease to a particular HLA DQ alpha/beta heterodimer. J Exp Med 1989;169(1): 345-350.