Celiac Disease (Sprue) 

Updated: Jul 25, 2019
Author: Stephan U Goebel, MD; Chief Editor: BS Anand, MD 

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]

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), international normalized ratio (INR)

  • Stool examination - Fat malabsorption

  • Oral tolerance tests - Lactose intolerance

  • Serology - Immunoglobulin A (IgA) antibodies

Patients diagnosed with celiac disease should be examined for several 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]

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.

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 Disease, Anatomy of the Digestive System, and Canker Sores.

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 small 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. Autoantibodies to type 2 transglutaminase (TG2) is a hallmark of celiac disease.[61]  Absence of intestinal villi and lengthening of the 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]

Etiology

Celiac disease results from a combination of immunological responses to an environmental factor (gliadin) and genetic factors.[6, 7, 60]

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 the enteric epithelial cells, stimulating the proliferation of the 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 the histologic 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.

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

A 2018 systematic review and meta-analysis noted that celiac disease is a global public health concern.[3] The overall prevalence of this condition is 1.4% on the basis of serologic findings and 0.7% on the basis of biopsy findings.[3, 60] However, specific national population-based prevalence studies are needed because the prevalence of celiac disease varies with factors such as sex, age, and location.[3]

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.

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.

 

Presentation

History

The manifestations of untreated celiac disease can be divided into gastrointestinal symptoms and extraintestinal symptoms.

Gastrointestinal symptoms

Diarrhea is the most common symptom in untreated celiac disease and is present in 45-85% of all patients. Diarrhea caused by celiac disease is due to the maldigestion and malabsorption of nutrients. The stools might be watery or semiformed, light tan or gray, and oily or frothy. The stools have a characteristic foul odor. In infants and young children, extensive diarrhea can lead to severe dehydration, electrolyte depletion, and metabolic acidosis.

Malabsorption of ingested fat (steatorrhea) results in the delivery of excessive dietary fat to the large bowel. This results in the production of hydroxy fatty acids by bacteria, which causes secretion of fluids into the intestinal lumen.

Flatulence (28% of patients) and borborygmus (35-72% of patients) results from the release of gas by the intestinal bacterial flora feasting on undigested and unabsorbed food materials and often becomes excessive or even explosive.

Weight loss (present in 45% of all patients) is variable because some patients might compensate for the malabsorption by increasing their dietary intake. In infants and young children with untreated celiac disease, failure to thrive and growth retardation are common.

Weakness and fatigue (prevalence 78-80%) are usually related to the general poor nutrition. In some patients, severe anemia can contribute to fatigue. Occasionally, severe hypokalemia due to the loss of potassium in the stool can cause muscle weakness.

Severe abdominal pain (prevalence 34-64%) is unusual in patients with uncomplicated celiac disease. However, abdominal bloating or cramps with excessive malodorous flatus is a common complaint.

Extraintestinal symptoms

Anemia (10-15% of patients) is usually due to the impaired absorption of iron or folate from the proximal small intestine. In severe celiac disease with ileal involvement, absorption of vitamin B-12 may also be impaired.

A bleeding diathesis is usually caused by prothrombin deficiency due to the impaired absorption of fat-soluble vitamin K.

Osteopenia and osteoporosis (prevalence 1-34%) may develop for several reasons, including defective calcium transport by the diseased small intestine, vitamin D deficiency, and binding of luminal calcium and magnesium to the unabsorbed dietary fatty acids.

Neurologic symptoms (frequency 8-14%) that result from hypocalcemia include motor weakness, paresthesias with sensory loss, and ataxia. Seizures might develop because of cerebral calcifications.[1]

Skin disorders, including dermatitis herpetiformis (a pruritic papulovesicular skin lesion involving the extensor surfaces of the extremities, trunk, buttocks, scalp, and neck), is associated in 10-20% of patients with celiac disease.

Hormonal disorders, such as amenorrhea, delayed menarche, and infertility in women and impotence and infertility in men, have been described.

Physical Examination

Physical examination findings may reveal the following:

  • Abdominal examination shows a protuberant and tympanic abdomen due to distention of the intestinal loops with fluids and gas. Ascites occasionally can be detected in patients with severe hypoproteinemia.

  • Evidence of weight loss, including muscle wasting or loose skin folds

  • Orthostatic hypotension

  • Peripheral edema

  • Ecchymoses

  • Hyperkeratosis or dermatitis herpetiformis

  • Cheilosis and glossitis

  • Evidence of peripheral neuropathy

  • Chvostek sign or Trousseau sign

 

DDx

 

Workup

Approach Considerations

The diagnosis of celiac disease is confirmed via histopathologic evaluation of duodenal biopsy specimens.[7]  Corroboration comprises evidence of small intestinal villous atrophy in the presence of celiac autoantibodies and/or an unequivoval response to a gluten-free diet.[60] Controversy exists regarding making the diagnosis without biopsy in specific cases, particularly in the pediatric population.[7]

In 2013, The American College of Gastroenterology (ACG) issued clinical guidelines regarding the diagnosis and treatment of celiac disease, including the following[2] :

  • Patients should be tested prior to being placed on a gluten-free diet

  • Antibody testing, especially immunoglobulin A anti-tissue transglutaminase antibody (IgA TTG), is the best first test, 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

  • Patients diagnosed with celiac disease should be examined for deficiencies, including low bone density (BMD)

  • 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

  • Patients in whom celiac disease is highly likely despite absence of prior testing should be treated as though they have the disease

  • Although most patients get better on a gluten-free diet, a systematic evaluation is needed for those who do not

The 2018 College of Family Physicians of Canada released their recommendations for managing bone health in adult and pediatric patients with celiac disease, including the following[55] :

Adults

  • Adults with malabsorption should undergo BMD testing at diagnosis as well as be evaluated for their levels of calcium, phosphate, and vitamin D. If the BMD results are normal at diagnosis, consider follow-up testing 2-3 years after starting a gluten-free diet.

  • At diagnosis with celiac disease, patients should be provided with counseling by dieticians with expertise not only in gluten-free diets but also in nutritional requirements for restoration of bone health. Optimal daily intake of recommended levels of calcium and vitamin should be from dietary sources (especially dairy) whenever possible.

  • Encourage patients to participate in weight-bearing exercises, limit alcohol intake, and avoid tobacco use.

  • Adults without malabsorption but who are at high risk of bone disease should also undergo BMD testing at diagnosis with celiac disease.

  • Those with subclinical or asymptomatic celiac disease should have a gluten-free diet and adequate calcium and vitamin D supplementation. After 1 year of such treatment, these patients should undergo BMD evaluation before further management.

  • Osteoporotic/osteopenic patients at diagnosis with celieac disease or individuals nonadherent to a gluten-free diet should have repeat BMD testing after 1-2 years on a gluten-free diet with calcium and vitamin D supplementation. An gluten-free expert dietician should routinely assess patients for adherence to this diet. 

Children and adolescents

  • Routine BMD is unnecessary in pediatric patients diagnosed with celiac disease at a young age. At diagnosis, management with adherence to a gluten-free diet as well as monitoring of growth and vitamin D levels are sufficient.

  • Consider BMD testing in children diagnosed with celiac disease who present with growth failure, severe malabsorption, prolonged diagnostic delay, or clinical evidence of bone disease. Repeat BMD testing every 1-2 years until the findings are normal, particularly in teenaged patients.

  • Children with inadequate sun exposure and insufficient dietary intake of calcium and vitamin D at diagnosis should undergo vitamin D studies and receive vitamin D supplementation, as needed. As with adult patients, provide counseling regarding adequate dietary intake of calcium and vitamin D, as well as weight-bearing exercises.

The College of Family Physicians of Canada also noted that "the role of antiresorptive medications in reducing the risk of fractures in patients with CD also remains unclear," and that the decision regarding use of hormone replacement therapy in perimenopausal women be individualized.[55] Therefore, clinicians should follow the guidelines from major gastroenterology, endocrinology, and dietetic associations. In patients adhering to 1-2 years of a gluten-free diet with adequate calcium and vitamin D supplementation who show persistent signs of osteoporosis, consider adding specific osteoactive therapies.[55]

See also the Guidelines section for the 2019 European Society for the Study of Coeliac Disease (ESsCD) updated guidelines for the management of celiac disease (CD) in adults and children.[62, 63]

Current screening guidelines for detecting undiagnosed cases of celiac disease using questionnaire-based, case-finding strategies failed to identify the majority of pediatric cases in a Swedish population-based screening study.[14, 15]  The study consisted of prediagnosis questionnaire responses about celiac disease–associated symptoms and conditions from 7054 children aged 12 years and 6294 of their parents.

Celiac disease was confirmed by small-bowel biopsy in 153 (2.1%) children from a group of 192 (2.7%) with elevated levels of tissue transglutaminase–immunoglobulin A or tissue transglutaminase–immunoglobulin G.[15]  The frequency of celiac disease detected was similar among children with and those without any associated celiac disease symptoms (2.1% in both groups) or celiac disease–associated conditions (3.6% vs 2.1%, respectively).[14, 15]  The sensitivity of this case-finding questionnaire was 38%, the specificity was 63%, the positive predictive value was 2%, and the negative predictive value was 98%.[15]

A study that assessed the prevalence of serologic markers of celiac disease in Italian patients referred to a rheumatology outpatient clinic found a high prevalence of antibodies to celiac disease.[56] The investigators suggested patients who present with rheumatologic features should be considered for screening for celiac disease.

Laboratory Studies

Patients with type 1 diabetes mellitus, Down syndrome, or Turner syndrome have an increased incidence of celiac disease. The mean prevalence ratio for coexisting type 1 diabetes and celiac disease is an estimated 8%, although this is likely an underestimation owing to subclinical or asymptomatic celiac disease.[58]

Electrolytes and chemistries

Electrolyte imbalances, such as hypokalemia, hypocalcemia, hypomagnesemia, and metabolic acidosis, can develop. Evidence of malnutrition, such as hypoalbuminemia, hypoproteinemia, hypocholesterolemia, and a low serum carotene level, might be present.

Hematologic tests

Anemia due to deficiency in iron, folate, and, rarely, vitamin B-12 might be present. A low serum iron level is common. A systematic review of 18 studies comprising 2,998 patients with iron-deficiency anemia found that the prevalence of biopsy-confirmed celiac disease in these patients was about 1 in 31.[59]

The prothrombin time (PT) might be prolonged and the international normalized ratio (INR) may be elevated because of malabsorption of vitamin K.

Stool examination

The typical bulky, greasy appearance and rancid odor of stools suggests malabsorption of fat. Findings from a Sudan stain of the stool might reveal fat droplets.

For a more quantitative measurement of fat absorption, a 72-hour fecal fat collection is frequently helpful in documenting steatorrhea.

Oral tolerance tests

Excretion of breath hydrogen, a product of bacterial fermentation of unabsorbed lactose, is often elevated in celiac disease.

The oral D-xylose tolerance test can reveal carbohydrate malabsorption. D-xylose is absorbed preferentially in the proximal small intestine and excreted unmetabolized in the urine. In untreated celiac disease, urinary D-xylose excretion and peak blood xylose levels are depressed.

Lactose tolerance is another oral tolerance test.

Serology

The most sensitive and specific antibodies for the confirmation of celiac disease are tissue transglutaminase IgA (tIgA), endomysial IgA, and reticulin IgA and correlate with the degree of mucosal damage. As the incidence of selective IgA deficiency is higher among patients with celiac disease, total IgA serum concentrations should be determined. If the patient is IgA deficient, tissue transglutaminase IgG can be measured.

The presence of serum IgA antibody to endomysium in untreated celiac disease has higher sensitivity and higher specificity than antigliadin antibodies. However, serum IgA antiendomysial antibody often becomes undetectable after 6-12 months of gluten withdrawal. Persistently elevated IgA endomysial and tissue transglutaminase antibodies for 12 months usually indicate poor compliance with a gliadin-free diet.

Seronegative celiac disease has been reported in 6.4-9.1% of patients with normal IgA serum concentrations; however, these patients are either elderly or have severe disease.

Genetic testing

Genetic testing with confirmatory serology may streamline the diagnosis of celiac disease. In a study that included 1494 women and 1540 men from the general Australian population, along with 356 volunteers who had biopsy-confirmed celiac disease, Anderson et al assessed the ability of HLA-DQ genotyping and serology to estimate the prevalence of celiac disease.[16, 17] Of those with biopsy-confirmed celiac disease, 91.3% had HLA-DQ2.5, 5.3% had HLA-DQ8 but not HLA-DQ2.5, and 2.0% had HLA-DQ2.2 but not HLA-DQ2.5 or HLA-DQ8; 5 patients lacked all 3, but 4 were found to have normal small bowel histology despite prolonged gluten challenge.

The prevalence of celiac disease in the general community, on the basis of the presence of 1 of these HLA-DQ types and positive tissue transglutaminase (TG)-2 serology, was approximately 1.3% in both women and men.[17] Confirmatory testing yielded positive results in 26 subjects (13 women and 13 men) with elevated TG-2 IgA levels, all of whom had HLA-DQ2.5. In addition, test results were positive in all 21 subjects (10 women and 11 men) with raised levels of TG-2 IgA, deamidated gliadin peptide (DGP) IgG, and DGP IgA, all of whom had HLA-DQ2.5.[17]

The authors developed a series of diagnostic algorithms to compare costs and resource utilization.[17] In the most cost-effective one, biopsies are reserved for patients with positive results on composite TG-2/DGP IgA/DGP IgG screening who are confirmed to be genetically susceptible to celiac disease and show abnormalities on confirmatory TG-2 IgA, DGP IgG, or DGP IgA testing. With this model, cost per case diagnosed is reduced by 38% in women and 25% in men, and gastroscopies are reduced by 38% in women and 65% in men.[17]

Imaging Studies

Small bowel barium 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.

Procedures

Upper endoscopy with at least 6 duodenal biopsies is considered the criterion standard to help establish a diagnosis of celiac disease. Serology and endoscopy should be considered, especially in patients presenting with classical symptoms, evidence of malabsorption, and endoscopic findings, including mucosal fold scalloping, reduced mucosal folds, and mosaic pattern.

Histologic Findings

Celiac disease primarily involves the mucosa of the small intestine. The submucosa, muscularis, and serosa are usually not involved. The villi are atrophic or absent with a decreased villous-to-crypt ratio (normal ratio, 4-5:1) and crypts are hyperplastic. The cellularity of the lamina propria is increased with a proliferation of plasma cells and lymphocytes. The number of intraepithelial lymphocytes per unit length of absorptive epithelium is increased (normal intraepithelial lymphocyte to epithelial cell ratio, 1:10).

Staging

Histologically, duodenal biopsies can be graded into the following 5 stages:

  • Stage 0 - Normal

  • Stage 1 - Increased percentage of intraepithelial lymphocytes (>30%)

  • Stage 2 - Characterized by an 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

 

Treatment

Medical Care

Diet

The primary management of celiac disease is dietary, but research into novel nondietary therapy is ongoing.[6, 7] Complete elimination of gluten-containing grain products (including wheat, rye, and barley) is essential to treatment.[18, 55, 57]  Although the majority of patients will celiac disease respond to a gluten-free diet, persistent/recurrent symptoms affect up to 20%.[60] Moreover, complete avoidance of gluten-containing grain products is relatively difficult for patients to achieve and maintain because certain products, such as wheat flour, are virtually ubiquitous in the American diet.

To facilitate elimination of gluten from the diet, the US Food and Drug Administration (FDA) has released rules providing uniform food-label definitions of “gluten-free.”[19, 20] By these rules, foods so labeled—as well as those that claim to contain “no gluten” or to be “free of gluten” or “without gluten"—must contain fewer than 20 parts of gluten per million. The European Union and Canada have implemented the same standards.[19]

After an initial period of avoidance, oats might be reintroduced into the diet of patients with celiac disease. These patients should be monitored carefully for recurrent symptoms. Careful and extensive indoctrination of the patient by the physician and the dietitian is often necessary to achieve full compliance.

Timing of gluten introduction

Two studies have suggested that the timing of gluten exposure does not affect the likelihood of developing celiac disease in children at high risk for the condition.[21, 22, 23]  The first study, which examined whether early exposure to gluten was protective against celiac disease, involved 944 children who were positive for the human leukocyte antigen (HLA) haplotype DQ2 or DQ8 and had at least one first-degree relative with celiac disease. Starting at age 16 weeks and continuing daily for 8 weeks, the infants received either 200 mg of vital wheat gluten mixed with 1.8 g lactose (the equivalent of 100 mg of immunologically active gluten) or placebo.[21, 22]

The children were followed up at age 3 years, at which time the cumulative incidence of celiac disease was 5.9% in the gluten group and 4.5% in the placebo group. It was also found that among girls, the cumulative incidence of celiac disease was higher in the gluten group than in the placebo group (8.9% vs 5.5%, respectively), although no such difference was found between boys in the two groups. Another finding was that the duration of breastfeeding (ie, whether the breastfeeding was exclusive or whether it was continued during gluten introduction) had no significant effect on the development of celiac disease.[21, 22]

The second study looked at whether delayed timing of gluten introduction was protective. More than 550 children who were positive for HLA-DQ2 and/or HLA-DQ8 and had at least one first-degree relative with celiac disease were randomized to be introduced to gluten-containing food at either age 6 months or age 12 months. By age 2 years, the incidence of overt celiac disease was 12% in the early gluten group and 5% in the late group, but by age 5 years, the incidence in both groups was 16%. Celiac disease autoimmunity was also more prevalent by age 2 years in the early gluten group than in the late group (16% vs 7%, respectively), but again evened out (21% vs 20%, respectively) by age 5 years.[21, 23]

Thus, the later introduction of gluten in this study did not seem to affect the risk of celiac disease but may have delayed its onset, with the median age of diagnosis being 26 months in the early group and 34 months in the late group. Similar to the first study, the duration of breastfeeding did not appear to affect the risk of celiac disease in either group.[21, 23]

Corticosteroids

A small percentage of patients with celiac disease fail to respond to a gluten-free diet. In some patients who are refractory, corticosteroids might be helpful. In patients who fail to respond to corticosteroids, other comorbid conditions, such as lymphomas of the small intestine, have to be ruled out.

Consultations

Consider consultations with a dietitian and nutritionist.

 

Guidelines

Guidelines Summary

In June 2019, the European Society for the Study of Coeliac Disease (ESsCD) released updated guidelines for the management of celiac disease (CD) and other gluten-related disorders in adults and children.[62, 63] Their strong CD recommendations are outlined below.

Who should be tested for celiac disease?

Adult patients with symptoms, signs, or laboratory evidence suggestive of malabsorption: Test with serology for CD.

Patients with unexplained elevation of serum aminotransferase levels: Exclude CD.

Patients with type 1 diabetes: Screen regularly for CD.

Workup

Serology

IgA-TG2 (immunoglobulin A-tissue transglutaminase 2) antibody is the preferred single test for CD detection at any age. Concurrently measure total IgA level with serology testing to determine whether IgA levels are sufficient.

At diagnosis and follow-up, perform IgG-based testing (IgG-DGPs [deamidated gliadin peptides] or IgG-TG2) in patients with selective total IgA-deficiency.

Perform all diagnostic serologic testing while patients are on a gluten-containing diet.

Antibodies directed against native gliadin (AGA) are not recommended for primary CD detection.

Endoscopy and histopathology

When CD is suspected, obtain biopsies even with a normal endoscopic appearance of the duodenum.

Duodenal biopsy is an essential component of the diagnostic evaluation for adults with suspected CD and is recommended to confirm the diagnosis. Multiple duodenal biopsies (at least four of the second part of duodenum) are recommended for confirmation.

An increase in intraepithelial lymphocyte (IEL) infiltration in the absence of villus atrophy (VA) in duodenal biopsies (Marsh 1) is not specific for CD; exclude other causes.

Helicobacter pylori infection is often associated with Marsh 1 histology; its eradication may normalize the duodenal IEL count. Obtain concomitant gastric biopsies or perform serology when H pylori is suspected.

If CD is highly suspected, perform duodenal biopsy even if the serology is negative.

HLA-DQ2/8 typing

Avoid routine use of HLA-DQ2/DQ8 testing in the initial diagnosis of CD. Include the results of such testing with a caution that patients at risk should be serologically tested for CD without changing their diet.

Use HLA-DQ2/DQ8 testing to rule out CD in selected clinical situations, including: (a) Marsh 1-2 histology in seronegative patients; (b) evaluation of patients not tested for CD before initiation on a gluten-free diet (GFD); (c) discrepant results of celiac-specific serology and histology.

Other diagnostic tests

Video capsule endoscopy (VCE) is not used for the initial diagnosis of CD except for patients with positive celiac-specific serology who are unwilling/unable to undergo endoscopy with biopsy. VCE is important in detecting complications associated with CD.

Intestinal-permeability tests are neither sensitive nor specific and are not recommended for CD diagnosis.

Serum intestinal fatty acid binding protein (I-FABP) might be useful in identifying dietary nonadherence and unintentional gluten intake.

Diagnostic confirmation

Diagnostic confirmation of CD in adults and in some children should be based on clinical data, positive serology, and duodenal histology.

Improvement of symptoms or exacerbation after gluten re-introduction has a very low predictive value for CD and should not be used for diagnosis in the absence of other supportive evidence.

A positive CD-specific serology in patients with VA confirms the CD diagnosis.

In case of an elevated TG2-titer and normal histology, a pathologist familiar with CD should review the biopsies. Repeat the biopsy after gluten challenge if the patient was not on gluten-containing diet before testing. HLA-DQ2/8 typing is mandatory. Testing for other antibodies (eg, DGP and/or endomysium [EMA]) may be of added value.

Seronegative CD requires careful assessment with HLA-DQ2/8 testing and a response to a GFD after excluding other causes of seronegative VA. Coeliac serology, both IgA- and IgG-based, should be negative.

In patients who are already following GFD prior to testing, serology and HLA typing are needed. If serology is positive, then biopsy is the next step. Perform a gluten challenge when serology is negative but HLA DQ2/DQ8 is positive.

Dietary management

Patients with CD should adhere to a lifelong GFD. The majority of CD patients safely tolerate oats; introduction of oats into the diet should be cautious, and monitor patients for possible adverse reaction.

Refer patients with CD to a dietitian who is well-trained concerning CD to get a detailed nutritional assessment, education on the GFD, and subsequent monitoring.

Newly diagnosed adult CD patients should undergo testing to uncover deficiencies of essential micronutrients (eg, iron, folic acid, vitamins D and B12).

Advise patients to eat a high-fiber diet supplemented with whole-grain rice, maize, potatoes, and ample vegetables.

Follow-up

Monitor CD patients regularly for persistent or new symptoms, adherence to GFD, and assessment for complications. Base monitoring of GFD adherence on a combination of history and serology. Monitoring of CD patients should include verification of the normalization of laboratory abnormalities detected during the initial investigation.

Dietary revision should be performed by a dietitian with special expertise in CD especially in slow-responders to exclude gluten contamination.

A normal anti-TG2 level at follow-up does not predict recovery of VA.

A follow-up duodenal biopsy is recommended for monitoring in cases of lack of clinical response or relapse of symptoms despite a GFD.

CD patients who are known to be hyposplenic should receive the pneumococcal vaccine.

Measure bone density in those at high risk of osteoporosis at diagnosis, especially in those with malabsorption or those at high risk if there is a long delay in diagnosis, or there are clinical presentations suggestive of bone disease. In others, not later than age 30-35 years and then to be repeated at 5-year intervals. Use a shorter interval (2-3 years) in case of low bone density on index measurement, evidence of ongoing VA, or poor dietary adherence.

Slow-responders and refractory CD (RCD)

Carefully evaluate patients showing slow response to exclude dietary inconsistencies and also identify other specific etiologies. The evaluation should include review of the initial diagnosis, celiac serology, a dietary review, and a follow-up duodenal biopsy.

Distinguish RCD-I from RCD-II to select appropriate management and determine the prognosis. T-cell flow cytometry is the most reliable method to make a distinction between RCD-I and RCD-II.

Closely monitor the nutritional status of RCD patients. Nutritional support including parenteral nutrition forms an essential part of the management.

Confidently exclude enteropathy-associated T cell lymphoma (EATL) before initiating pharmacotherapy in RCD-II. RCD-II patients need to be treated in referral centers by an experienced gastroenterologist in CD with a hematologist.

Exclude EATL in any CD patient with abdominal pain, fever, obstruction, anemia, gastrointestinal bleeding, or unexplained weight loss.

In EATL, debulking surgery for large ulcerated small bowel tumors is recommended for limiting the risk of perforation or bleeding during chemotherapy.

Special issues about children and adolescents

Duodenal histology in some children is recommended to confirm the diagnosis of CD.

Introduce a GFD only when the CD diagnosis has been made conclusively.

A gradual, structured transfer of medical care of an adolescent with CD to adult care is recommended. Include as the minimum written information on the base of diagnosis, follow-up, anthropometric data, comorbidities, and dietary adherence.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Corticosteroids might be indicated in patients with refractory celiac disease.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Sterapred)

Can be used in patients with refractory celiac disease. Might decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. The usual starting dose of its metabolite prednisolone is 40 mg to 60 mg daily.

 

Questions & Answers

Overview

What is celiac disease?

What happens when patients with celiac disease ingest gliadin?

What are the GI symptoms of celiac disease?

What are the extraintestinal symptoms of celiac disease?

What causes a bleeding diathesis in celiac disease?

Which physical findings suggest celiac disease?

What are the American College of Gastroenterology (ACG) recommendations for the diagnosis of celiac disease?

Which lab tests may be performed in the diagnosis of celiac disease?

Which conditions should screened in patients with confirmed celiac disease?

What is the role of imaging studies in the diagnosis of celiac disease?

How is celiac disease histologically graded?

What is the primary treatment for celiac disease?

What is celiac disease?

What is the pathophysiology of celiac disease?

What are the causes of celiac disease?

What is crucial for the pathogenesis of celiac disease?

What is the role of gliadin in the etiology of celiac disease?

What is the role of immunoglobulin A (IgA) antibodies in the etiology of celiac disease?

What is the role of cell-mediated immune responses in the pathogenesis of celiac disease?

What is the role or genetics in the etiology of celiac disease?

How does the prevalence of celiac disease vary by race and sex?

What is the prevalence of celiac disease in the US?

What is the incidence of undiagnosed celiac disease in the US?

What is the global prevalence of celiac disease?

How does the prevalence of celiac disease vary by age?

What is the prognosis of celiac disease?

What are the morbidities of celiac disease?

What are possible complications of celiac disease?

What are the risks of untreated celiac disease during pregnancy?

What causes short stature in patients with celiac disease?

What are symptoms of celiac disease malabsorption?

Which malignant diseases are associated with celiac disease?

What are the symptoms of refractory celiac disease?

What are the types of refractory celiac disease?

Presentation

What are the manifestations of untreated celiac disease?

What is the most common symptom in untreated celiac disease?

What is the pathophysiology of ingested fat malabsorption in celiac disease?

What causes flatulence and borborygmus in celiac disease?

Why is weight loss variable in celiac disease?

What causes weakness and fatigue in celiac disease?

How is abdominal pain characterized in celiac disease?

What causes anemia in celiac disease?

What causes a bleeding in celiac disease?

What causes osteopenia and osteoporosis in celiac disease?

What are the neurologic symptoms of celiac disease?

What are the dermatologic symptoms of celiac disease?

Which hormonal disorders are associated with celiac disease?

What are the physical findings characteristic of celiac disease?

DDX

What are the differential diagnoses for Celiac Disease (Sprue)?

Workup

How is the diagnosis of celiac disease confirmed?

What are the 2013 American College of Gastroenterology (ACG) guidelines for the diagnosis and treatment of celiac disease?

What are the College of Family Physicians of Canada recommendations for managing bone health in adult and pediatric patients with celiac disease?

What is the efficacy of screening strategies for undiagnosed celiac disease?

What is the role of small-bowel biopsy in the diagnosis of celiac disease?

Which conditions increase the risk for celiac disease?

Which lab findings suggest celiac disease?

What is the role of hematologic tests in the diagnosis of celiac disease?

What is the role of stool exam in the diagnosis of celiac disease?

What is the role of oral tolerance tests in the diagnosis of celiac disease?

Which antibody tests are used to confirm the diagnosis of celiac disease?

What is the role of antigliadin and immunoglobulin A (IgA) antibody testing in the diagnosis of celiac disease?

What is the prevalence of seronegative celiac disease?

What is the role of genetic testing in the diagnosis of celiac disease?

What is the purpose of diagnostic algorithms for celiac disease?

What is the role of radiography in the diagnosis of celiac disease?

What is the role of upper endoscopy in the diagnosis of celiac disease?

Which histologic findings are characteristic of celiac disease?

What are the histologic stages of celiac disease?

Treatment

What is the primary treatment for celiac disease?

Which food labeling definitions are important in the management of celiac disease?

When are oats reintroduced into the diet in patients with celiac disease?

How does the timing of gluten introduction affect the risk of developing celiac disease?

What is the role of corticosteroids in the treatment of celiac disease?

Which specialist consultations are helpful for patients with celiac disease?

Medications

What are the goals of drug treatment for celiac disease?

Which medications in the drug class Corticosteroids are used in the treatment of Celiac Disease (Sprue)?