Celiac Disease (Sprue)

Updated: Jan 09, 2017
  • Author: Stephan U Goebel, MD; Chief Editor: BS Anand, MD  more...
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Overview

Practice Essentials

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

Gastrointestinal symptoms

Gastrointestinal symptoms may include the following:

  • 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

Extraintestinal symptoms

Extraintestinal symptoms may include the following:

  • 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 [1]
  • 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.

Physical examination

A physical exam may reveal the following:

  • A protuberant and tympanic abdomen
  • Evidence of weight loss
  • Orthostatic hypotension
  • Peripheral edema
  • Ecchymoses
  • 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.

Diagnosis

Laboratory tests

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]

Imaging studies

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.

Management

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.

See Treatment and Medication for more detail.

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Background

Celiac disease, also known as 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). [4]

For patient education resources, see Digestive Disorders Center and Oral Health Center, as well as Celiac DiseaseAnatomy of the Digestive System, and Canker Sores.

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Pathophysiology

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 occurs 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. [5]

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Etiology

Celiac disease results from a combination of immunological responses to an environmental factor (gliadin) and genetic factors. [6, 7]

Immune mechanisms

The interaction of alcohol-soluble gliadin in wheat, barley, and rye 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. [8]

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.

Genetic factors

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 the expression of the proinflammatory cytokine interferon gamma and the activation of CD4+ T lymphocytes.

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Epidemiology

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] : 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). [9]  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). [9]

International statistics

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 demographics

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. [12]

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.

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Prognosis

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.

Morbidity/mortality

Although rarely lethal, celiac disease is a significant and often debilitating maldigestive and malabsorption syndrome affecting multiple organ systems.

Patients with celiac 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):

  • Chronic diarrhea
  • Steatorrhea
  • Abdominal bloating or cramps
  • Flatulence
  • Weight loss
  • Fatigue
  • Anemia
  • Bleeding diathesis
  • Osteopenia
  • Seizure disorders
  • Stunted growth

Complications

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, which has 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. [13]

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.

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