Condition

Celiac disease (CD) is an immune-mediated disorder triggered in genetically-susceptible individuals by ingestion of foods containing gluten, a family of proteins found in wheat, rye, barley, and related grains.¹ The prevalence of CD in the United States has been estimated at approximately one percent,² but appears to be increasing, for reasons that are not clear.³ Risk factors for CD include family history, trisomy 21, Turner syndrome, and Williams syndrome, as well as several autoimmune diseases.

Clinical signs of CD include weight loss, iron deficiency anemia, aphthous ulcers, osteomalacia, dermatitis herpetiformis (a rash due to gluten-sensitivity), and gastrointestinal symptoms, including diarrhea and abdominal bloating. The diagnosis of CD can be challenging because the clinical spectrum of the disease varies, and some individuals present with mild symptoms.⁴

CD causes enteropathy of the small intestine resulting in poor absorption of nutrients. Malabsorption may result in several of the aforementioned clinical signs, including iron deficiency anemia, osteomalacia, and weight loss. Young children, in particular, are susceptible to failure to thrive, stunted growth, and delayed puberty.⁵ In women, folate deficiency secondary to CD may lead to poor birth outcomes, including developmental disorders. In the long-term, untreated CD increases the risk for non-Hodgkin's lymphoma, certain gastrointestinal cancers, and all-cause mortality.⁴

The only effective treatment for CD is avoidance of gluten in the diet. Timely diagnosis may be the most important component in the management of CD.

Diagnostic Strategies

A number of diagnostic methods have been developed; the validity and acceptability of some of these methods, particularly newer tests, which include combination tests and algorithms, remain controversial. Methods include various serology tests, HLA typing, video capsule endoscopy, and endoscopic duodenal biopsy (often considered the gold standard). Serology tests include anti-gliadin antibodies (AGA), IgA & IgG; anti-tissue transglutaminase (tTG), IgA & IgG; Endomysial antibodies (EmA), IgA; and the deamidated gliadin peptide (DGP) Antibodies, IgA & IgG. These tests are often used by providers as a panel in order to increase specificity and prevent false positives or increase sensitivity and prevent false negatives. All methods other than HLA typing require that the patient maintain a gluten containing diet during the diagnostic process. Commonly used diagnostic methods are described below.

Anti-gliadin antibodies (AGA), IgA & IgG. Gliadin is one of the two groups of proteins that constitute gluten. AGA determination was used as a diagnostic tool in the 1990s, as it has high sensitivity for CD.⁶ However, the test has low specificity, because anti-gliadin IgG is found in both acute and chronic common intestinal childhood diseases. In 2007, the World Gastroenterology Organization recommended against using these tests.⁷ In 2009, the UK National Institute for Clinical Excellence (NICE) also recommended against using the tests.⁸ As AGA tests are no longer recommended, they are not addressed in this systematic review.

Anti-tissue transglutaminase (tTG), IgA. Tissue transglutaminase is an enzyme that causes the crosslinking of certain proteins. Anti-tTG, IgA is the single test preferred by the American College of Gastroenterology (ACG) for the detection of celiac disease in those over the age of 2 years.⁵ These tests are also included in the algorithms of all recent guidelines. It is important to note that IgA deficiency is more prevalent in CD patients than in the general population; therefore, other tests may be ordered as an alternative in those who are IgA deficient.

Endomysial antibodies (EmA), IgA. The thin connective tissue layer that covers individual muscle fibers is called endomysium. When the intestinal lining is damaged, endomysial antibodies (EmA) develop. Most patients with active celiac disease and many with dermatitis herpetiformis have the IgA class of anti-EmA antibodies. Although this test is included in the algorithms of recent guidelines for diagnosis, it is not as widely used in the U.S. as in other countries, and many providers simply order a biopsy if the tTG levels are high. In addition, this test is less useful in individuals with low IgA.

Deamidated gliadin peptide (DGP) Antibodies. Elevated DGP antibodies are often seen in patients with celiac disease on a gluten-containing diet; this newer test may give a positive result in some individuals with CD who are anti-tTG negative, including children younger than 2 years old. Testing both DGP IgG and anti-tTG IgG is recommended by the ACG for those who have low IgA or IgA deficiency.⁵

Human leukocyte antigen (HLA) typing. Susceptibility to CD is linked to certain human leukocyte antigen (HLA) class II alleles, especially in the HLA-DQ region. HLA molecules are hypothesized to present gluten antigens to T-cells, which in turn induce tissue damage.⁹ Approximately 95 percent of patients with CD have the HLA-DQ2 heterodimer, while the remaining 5 percent of persons with CD have the HLA-DQ8 heterodimer.¹⁰ Since 25 percent to 40 percent of the U.S. population carries either the DQ2 or DQ8 gene, the presence of either is not pathognomonic for CD. However, lack of these heterodimers all but rules out CD and genetic susceptibility for the disorder. Thus, these genetic tests are routinely used to rule out CD and are part of the diagnostic algorithms recommended by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) and the ACG.¹¹

Video capsule endoscopy. In this procedure, a capsule containing a tiny camera is ingested by the patient, providing high quality visual evidence of CD. While not a traditional means of detecting CD, it is used in adults who seek to avoid biopsy. During Topic Refinement, Key Informants (KI) requested assessment of the evidence for this method in this report.

Endoscopic duodenal biopsy. Villous atrophy present on a duodenal biopsy and clinical remission when a gluten-free diet is followed represent the internationally accepted gold standard for CD diagnosis. The Modified Marsh criteria are utilized by most pathologists in evaluating histology findings from duodenal biopsy specimens for celiac disease diagnosis and progression of treatment during follow up.¹² The criteria are graded from 0-3 with grade 3 further subdivided to 3a, 3b, and 3c.^{13, 14} Patients with Marsh grade 0 have normal histologic findings and are very unlikely to have celiac disease. In Marsh grade 1 and 2, biopsy specimens demonstrate raised Intraepithelial lymphocytes (IELs>30 per enterocytes) alone and raised IELs with crypt hyperplasia respectively. These histologic outcomes may be found in celiac patients on treatment or in patients with dermatitis herpetiformis. However, grade 1 or 2 lesions alone in the absence of clinical or serology evidence are nonspecific and are suggestive, but not confirmatory, of celiac disease.¹⁵ Patients with Grade 3 lesions have raised IELs with crypt hyperplasia and a measure of villous atrophy. Grade 3a, 3b, and 3c, in addition to raised IELs with crypt hyperplasia, also have findings of partial villous atrophy, subtotal villous atrophy, and total villous atrophy respectively.¹⁴ Marsh grade 3 lesion is the classic celiac lesion and is characteristic, but not diagnostic, of celiac disease.¹⁶ Of note, some community physicians use a simple qualitative assessment of villous atrophy or elevation of intraepithelial lymphocytes to make a diagnosis rather than relying on Marsh criteria.

Obtaining properly oriented tissue samples can be difficult, patchy mucosal lesions can be missed, and limiting the portion of gut examined may risk missing the diagnosis of CD-related complications such as lymphoma and ulcerative jejunoileitis. Some patients and parents are concerned about the risk of adverse events such as perforations and bleeding. Patients may feel pain and discomfort, which is especially problematic for small children.

Combinations of the above. Many providers use a serology panel or sequential approach in order to prevent false positives that are associated with tests that don't work well under varying circumstances. The current systematic review compares the effectiveness of diagnostic tests, singularly and in combination.

Scope of the Review

Several systematic reviews and guidelines on diagnosis of CD have been published in the past decade, often with contradictory findings and recommendations. At least five recent guidelines for the diagnosis of CD have been published by recognized research/academic/medical bodies such as the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN)¹⁷ and ESPGHAN.¹¹

These clinical practice guidelines are complex and recommend different approaches to diagnosis. For example, some guidelines propose different sequences of tests for diagnosing population groups such as children versus adults, and symptomatic versus asymptomatic patients at increased risk (e.g. ESPGHAN). In addition, some guidelines (ACG and World Gastroenterology Organization [WGO]) uphold endoscopic biopsy as the gold standard for confirming diagnosis,^{5, 18} whereas other guidelines (ESPGHAN) explore the use of other tests to serve as substitutes for biopsy. The diagnosis of celiac disease is further complicated by lack of provider knowledge and variability in laboratory cut-off levels to indicate “positive” results. It is also unknown whether the same diagnostic criteria apply to different racial, ethnic, or other demographic subgroups, or if they may be incorrectly diagnosed or underdiagnosed. In addition, false positives and false negatives may have significant consequences: Positive diagnosis requires huge lifestyle changes, and undiagnosed CD can result in potential health harm (nutrient malabsorption, osteoporosis, and lymphoma).

This report compares the accuracy of the diagnostic methods listed above in children, adults, and sub-populations of interest to clinicians and patient groups. Diagnostic methods that are no longer included in guidelines or still in development (not approved in the U.S.) are beyond the scope of this project. Accuracy of serological tests and VCE are based on biopsy results as the reference standard. We also assess how biopsy results may vary by provider characteristics, technique, and the length of time the patient has consumed gluten. Finally, we report adverse events associated with invasive diagnostic methods (biopsy, VCE) and sequelae of false or indeterminate results of diagnosis. We provide below an analytic framework to illustrate the populations, interventions, outcomes, and adverse effects that guided the literature search and synthesis for this project (Figure 1).

Figure 1

Analytic framework, diagnosis of celiac disease. CD = celiac disease; FN = false negative; FP = false positive; IgA = immunoglobulin A; KQ = Key Question; LR+ = positive likelihood ratio; LR- = negative likelihood ratio; SES = socioeconomic status; TN (more...)

Key Questions

Four Key Questions guided this systematic review, as follows.

Key Question 1. What is the comparative effectiveness of the different diagnostic methods (various serological tests, HLA typing, video capsule endoscopy, used individually and in combination) compared with endoscopy with biopsy as the reference standard to diagnose celiac disease (CD) in terms of—

1. Accuracy: sensitivity, specificity, positive likelihood ratio (LR+), negative likelihood ratio (LR-), summary receiver operating characteristics (ROCs)?
2. Intermediate outcomes, such as clinical decisionmaking and dietary compliance?
3. Clinical outcomes and complications related to CD?
4. Patient-centered outcomes, such as quality of life (QOL) and symptoms?

Key Question 2. Does accuracy/reliability of endoscopy with duodenal biopsy vary by—

1. Pathologist characteristics (i.e., level of experience or specific training)?
2. Method (i.e., type or number of specimens)?
3. Length of time ingesting gluten before diagnostic testing?

Key Question 3. How do accuracy, (sensitivity, specificity, LR+, LR-, summary ROCs) and outcomes differ among specific populations (subgroups of Key Question 1), such as—

1. Symptomatic patients versus nonsymptomatic individuals at risk?
2. Adults (age 18 and over) versus children and adolescents?
3. Children under age 24 months versus older children?
4. Demographics, including race, genetics, geography, and socioeconomic status?
5. Patients with IgA deficiency?
6. Patients previously testing negative for CD?

Key Question 4. What are the direct adverse effects (i.e., bleeding from biopsy) or harms (related to false positives, false negatives, indeterminate results) associated with testing for CD?

In addition, we identify the following PICOTS (Populations, Interventions, Comparators, Outcomes, and Timing) for the Key Questions:

Population(s):

• For KQ 1, 2, and 4:
  • All populations tested for CD
• For KQ 3:
  • Patients with signs and symptoms of celiac disease, for example:
    • Diarrhea
    • Constipation
    • Dermatitis
    • Malabsorption (anemia, folate deficiency)
  • Asymptomatic individuals at risk of celiac disease
    • Family history
    • Type 1 diabetes
    • Auto-immune disease
    • Turner's syndrome
    • Trisomy 21
  • Children, under age 24 months vs older children & adolescents
  • Adults (aged 18+)
  • Ethnic and geographic populations
  • Low socioeconomic status (SES)
  • Patients with IgA deficiency
  • Patients previously testing negative for CD

Interventions:

• For KQ 1, 3, 4:
  • Endomysial antibodies (EmA) IgA test
  • Anti-tissue transglutaminase (tTG) IgA test
  • Deamidated gliadin poeptide (DGP) IgA antibodies
  • EmA IgG, tTG IgG, and DGP IgG tests for IgA deficient individuals
  • HLA typing
  • Video capsule endoscopy
  • Combinations of the above
• For KQ 2:
  • Endoscopy with biopsy

Comparators:

• For KQ 1, 3:
  • Endoscopy with duodenal biopsy
• For KQ 2:
  • Repeat biopsy

Outcomes:

• For KQ 1a, KQ2 and 3a-f, for Accuracy
  • Sensitivity
  • Specificity
  • PPV, NPV, FP, FN
  • Positive and negative likelihood ratios
• For KQ 1b, for Clinical decisionmaking
  • Additional testing for CD
  • Nutritionist advice on gluten-free diet
  • Follow up and monitoring by MD
• For KQ 1c, for Clinical outcomes and complications
  • Nutritional deficits
  • Persistence of villous atrophy on biopsy
  • Lymphomas
• For KQ 1d, for Patient-centered outcomes
  • Quality of life
  • Discomfort
  • Bloating
  • Abdominal pain
  • Depression
• For KQ 4, for Harms
  • Immediate AEs from biopsy
  • Psychological stress related to false positive results
  • Sequelae of false negatives or indeterminate results

Timing:

• For KQ 2
  • Length of time ingesting gluten before biopsy

Setting:

• For all KQs
  • Outpatient: Academic
  • Outpatient: Community

Organization of This Report

The remainder of this report presents the methods used to conduct the literature searches, data abstraction, and analyses; the results of the literature searches and analyses; the conclusions; and a discussion of the limitations as well as suggestions for future research.