Diagnosis of Celiac Disease (CD)
The clinical classification of CD has undergone a change; today, most experts agree with the following classification:
Classical
Mostly gastrointestinal symptoms
Atypical
Mostly nongastrointestinal symptoms—usually monosymptomatic or oligosymptomatic
Silent
No symptoms despite the presence of a characteristic intestinal lesion
Differential Diagnosis
CD presents a very complex and protean clinical picture, and there are many diseases with mucosal changes similar to those of CD.
Table. Conditions with Mucosal Changes Similar to Those in CD
- Tropical sprue
- Human immunodeficiency virus (HIV) enteropathy
- Combined immunodeficiency states
- Radiation damage
- Recent chemotherapy
- Graft-vs.-host disease
- Chronic ischemia
- Giardiasis
- Crohn's disease
- Eosinophilic gastroenteritis
- Zollinger-Ellison syndrome
- Autoimmune enteropathy
- Enteropathy-associated T-cell lymphoma
- Refractory sprue
- Collagenous sprue
(The last four are probably related to CD)
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Diagnostic Tests
Only endoscopy with biopsy of the small intestine plus a positive CD serology provide a definitive diagnosis. This is the gold standard.
Role of Endoscopy for Suspicion of Celiac Disease
Although endoscopy may provide an indication for intestinal biopsy, it may not be sufficiently sensitive to detect all manifestations of CD in a population.
The characteristic findings of an endoscopy include:
- Scalloped folds, fissures, and mosaic pattern
- Flattened folds
- Smaller size and or disappearing of folds with maximum insufflation
Intestinal Biopsy
Intestinal biopsies together with a positive serology represent the gold standard for diagnosing celiac disease.
Multiple biopsies are taken from the second or third part of the duodenum. Endoscopy has become the most convenient method of obtaining biopsies of the small-intestinal mucosa. Suction biopsy (Crosby capsule) provides the best samples.
Histological Characteristics of Celiac Enteropathy
CD affects the mucosa of the proximal small intestine, with damage gradually decreasing in severity towards the distal small intestine, although in severe cases the lesions can extend to the ileum. The degree of proximal damage varies greatly depending on the severity of the disease. The proximal damage may be very mild in "silent" cases, with little or no abnormality detectable histologically in the mid-jejunum. Abnormalities in the gastric and rectal mucosa may be observed in some cases.
Occasionally, the lesion in the duodenum/upper jejunum can be patchy, which may justify a second biopsy immediately in selected patients with positive endomysial antibody (EMA). However this is only warranted if all three samples of the first biopsy show a normal histology.
See original guideline document for Marsh's classification of small-intestinal lesions.
Use of Serum Antibodies to Diagnose Celiac Disease
- Immunoglobulin A (IgA) endomysial antibody (IgA EMA; highest diagnostic accuracy)
- IgA tissue transglutaminase antibody (IgA tTG)
- IgA antigliadin antibody (IgA AGA)
- IgG antigliadin antibody (IgG AGA)
Serologic studies for celiac disease can be divided into two groups, based on the target antigens:
- Anti-tTG antibody tests
- Antigliadin antibody tests
IgA EMA: IgA endomysial antibodies bind to endomysium, the connective tissue around smooth muscle, producing a characteristic staining pattern that is visualized by indirect immunofluorescence.
The test result is reported simply as positive or negative, since even low titers of serum IgA endomysial antibodies are specific for CD. The target antigen has been identified as tissue transglutaminase (tTG or transglutaminase 2).
IgA endomysial antibody testing is moderately sensitive and highly specific for untreated (active) CD.
Anti-tissue transglutaminase antibodies (IgA tTG): The antigen against which antiendomysial antibodies are directed is tTG. Anti-tTG antibodies are highly sensitive and specific for the diagnosis of CD.
Enzyme-linked immunosorbent assay (ELISA) tests for IgA anti-tTG antibodies are now widely available and are easier to perform, less observer-dependent, and less costly than the immunofluorescence assay used to detect IgA endomysial antibodies. The diagnostic accuracy of IgA anti-tTG immunoassays has been improved further by the use of human tTG in place of the nonhuman tTG preparations used in earlier immunoassay kits.
Antigliadin antibody assays (IgA AGA and IgG AGA): Gliadins are the major proteins of the wheat storage proteins collectively termed gluten.
Purified gliadin is readily available and is used as the antigen for ELISA tests to detect serum antigliadin antibodies.
Serum antigliadin antibody levels are frequently elevated in untreated CD, and antigliadin assays have been used for some years as a diagnostic aid.
Although these tests demonstrate moderate sensitivity and specificity, with the IgA tests being superior, their positive predictive value in the general population is relatively poor.
AGA tests are no longer routinely recommended, because of their lower sensitivity and specificity.
Key Symptoms
Adults: Gastrointestinal Symptoms
- Chronic diarrhea (most common symptom)
- Weight loss
- Anemia
- Abdominal distension
- Lassitude and malaise
Children: Gastrointestinal Symptoms
- Failure to thrive, weight loss, down-shift of weight or height centile, short stature
- Vomiting
- Diarrhea
- Recurrent abdominal pain
- Muscle wasting
- Irritable bowel
- Hypoproteinemia
- Irritability and unhappiness
Adults and Children: Nongastrointestinal Symptoms
- Iron deficiency/anemia
- Dermatitis herpetiformis
- Peripheral neuropathy
- Folic acid deficiency
- Reduced bone density
- Unexplained infertility
Consider CD in Cases of:
- Unexplained folic acid, iron, or B12 deficiency
- Reduced serum albumin
- Unexplained hypertransaminasemia
- Osteoporosis and osteomalacia
- Recurrent abdominal pain or bloating
- Skin rashes
Why is Celiac Disease Difficult to Diagnose?
- Alternative diagnoses (often irritable bowel syndrome)
- The condition may be oligosymptomatic or asymptomatic
- The condition may have latent periods
- Clinicians are "unaware" and there are several "myths":
- CD is rare
- CD occurs in Caucasians only
- CD occurs mostly in Europe and the USA
- CD occurs only in childhood
- CD can be cured after (a period of) treatment
Risks
An elevated risk for CD exists in:
- First-degree and second-degree relatives (5 to 15% basic, 10 to 30% if DQ2 or DQ8+; see section 3.1 in the original guideline document)
- Down's syndrome (12%)
- Autoimmune thyroid disease (5%)
- Chronic active hepatitis
- Type 1 diabetes mellitus (5 to 6%)
- Lymphocytic colitis (15 to 27%)
- Chronic fatigue syndrome (2%)
- Irritable bowel syndrome
Those With (Long-Term Untreated) CD Have an Elevated Risk For:
- Cancer (overall 1.3:1.0)
- Malignant lymphomas
- Small-bowel neoplasia
- Oropharyngeal tumors
- Unexplained infertility (12%)
- Osteoporosis (increased risk for classically symptomatic CD patients)
The Global Aspect
The diagnosis of CD can be made with different diagnostic technologies in different parts of the world, depending on the available resources, but the specificity and validity of the results may vary when tools poorer than those of the "gold standard" are used.
Depending on available resources, diagnostic options can be cascaded from a highly resourced setting in which the above gold standard can be used—endoscopy followed by small-bowel biopsy and specific serology for confirmation or case finding—to a situation in which very few resources are available and only the minimum can be done.
If biopsy is not available, "serology only" remains a feasible method for diagnosing CD; also because serological tests are cheaper than endoscopy and biopsy and their statistical value is very similar.
In the absence of a biopsy, the criteria are:
- The presence of auto-antibodies
- Gluten dependency of the auto-antibody titer
- Clinical symptoms, when present
- Improvements in symptoms and reduction in the anti-tTG antibody titer on a gluten-free diet
- In children, catch-up growth, when applicable
The easiest and cheapest serological test would be the dot ELISA. Once a bedside IgA anti tTG test becomes available and sufficiently sensitive and specific, it would be ideal for low-income regions.
If a geographic area has very limited resources, clinical aspects become the most important diagnostic tool. A rice-based or corn-based gluten-free diet (GFD) is the final and vital step in confirming a diagnosis of CD.
Table. Cascade for Diagnosing CD
- Autoantibodies and endoscopy with intestinal biopsy (gold standard)
- Endoscopy with intestinal biopsy
- Autoantibodies
- EMA or anti-tTG or both (depending on availability and experience)
- Dot ELISA
- Diagnosis based on "clinical aspects," with clinical improvement after a corn-based or rice-based GFD
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Although endoscopy is a very useful tool for detecting CD, it cannot be relied on as a single diagnostic procedure. The presence of markers of mucosal atrophy may be highly suggestive of CD in places where the disease is common, but in other areas of the world there may several differential diagnoses—for example, tropical sprue, malnutrition, heavy-chain disease, etc.).
Nevertheless, the procedure is very helpful when markers are elevated in the course of endoscopies ordered for other reasons. Then the endoscopist must be alert and proceed to intestinal biopsy.
Management of Celiac Disease
The current treatment for CD is a strictly gluten-free diet for life. In the gluten-free diet, wheat, barley, and rye are avoided. Oats are not toxic in >95% of patients with CD or dermatitis herpetiformis, but there is a small subgroup (<5%) for whom oats are not safe.
Additionally, there is a reluctance in some countries to advise liberal use of oats because of the difficulty in guaranteeing that commercially available oats will be free of contamination with other grains. Rice and corn can be part of a GFD.
Initial approach:
- Prescribe a "natural" gluten-free diet
- Refer to a dietician and/or support group (see web sites listed below)
- Screen for iron and folate deficiency
- Advise bone-density tests (in some cases)
- Advise vitamin D and calcium supplementation if the patient is osteoporotic
- Advise serological screening for first-degree and second-degree relatives
Most patients have a rapid clinical response to a gluten-free diet (within 2 weeks), although the rate of response varies. Patients who are extremely ill may require hospital admission, repletion of fluids and electrolytes, intravenous alimentation, and, occasionally, steroids. Patients should be encouraged to eat natural high-iron and high-folate foods, especially if a deficiency in these minerals is documented.
Patients should also have a consultation with a dietician who is knowledgeable about gluten-free diets. However, not all dieticians are familiar with the intricacies of a gluten-free diet, and for this reason local or national support groups provide most of the required information.
For adults, quality of life is improved on a gluten-free diet, even in those whose disease was detected by screening. Children on a gluten-free diet reported a quality of life comparable to that of a reference population. Adolescents have difficulty with dietary compliance.
The Gluten-Free-Diet
The most effective treatment is a rigorous GFD for life. This means no wheat, rye, or barley. Oats—provided they are pure and not contaminated with other grains (even minimal amounts of wheat, rye, or barley)—are safe to eat in >95% of cases.
Plain meat, fish, rice, corn, fruits, and vegetables do not contain gluten. Examples of foods that are safe to eat and those that are not can be found online. Useful online CD information sites are listed in sections 8 and 9 of the original guideline document.
A gluten-free diet is low in fiber. Patients should be advised to eat a high-fiber diet supplemented with whole-grain rice, maize, potatoes, and ample vegetables.
Correct any dietary deficiencies such as iron, folic acid, calcium, and (very rarely) B12 deficiency.
See Table 5 in the original guideline document for foods allowed in a gluten-free-diet.
Persistence of Symptoms
A common difficulty with the GFD is the presence of occult gluten in processed foods and/or medicines (although this is rare). The persistence of symptoms is almost always caused by continued ingestion of gluten.
Reasons for persistence of symptoms:
- (Inadvertent) gluten ingestion (this is the most common reason)
- Wrong diagnosis
- Lactose or fructose intolerance
- Other food intolerances
- Pancreatic insufficiency
- Microscopic colitis
- Bacterial overgrowth
- Collagenous colitis or collagenous sprue
- Irritable bowel syndrome
- Ulcerative jejunitis
- Enteropathy-associated T-cell lymphoma
- Refractory CD
The last three can be regarded as complications of long-lasting CD.
Refractory Celiac Disease
The diagnosis of refractory CD is considered in patients with features of CD who have persistent symptoms, villous atrophy, and failure to respond to a gluten-free diet. This may occur at presentation, or after an initial response to a gluten-free diet.
Refractory CD is considered to be a form of low-grade intraepithelial lymphoma, revealed by severe malabsorption that is not responsive to a gluten-free diet.
This diagnosis must be considered particularly in celiac disease patients who are diagnosed over the age of 50.
Screening for Celiac Disease
The current view is that there is not enough evidence to support a decision to carry out mass screening of the general population, nor is there enough evidence to assess the risks of undetected CD.
