Bowel Disorders Evaluation Rule-out Cascade*

Disorders of the lower gastrointestinal tract in adults and children are among the most common conditions and may pose a difficult diagnostic problem. They account for 1 in 20 of all general practitioner consultations and their symptoms are frequently ill-defined.¹ Those disorders include a wide range of pathologic conditions, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) that includes Crohn's disease (CD), ulcerative colitis (UC), and indeterminate colitis; microscopic colitis, infectious colitis, small intestinal bacterial overgrowth, celiac disease, and colon neoplasia (including colon cancer).² The most prevalent condition is IBS. Its prevalence in Europe and North America is estimated to be 10% to 15%.³ Prevalence of celiac disease increased at least four times during the last 50 years and approaches 0.9%.⁴ The incidence rate of Crohn’s disease increased from 0.1 (three decades ago) to 4.6 (in 2003) per 100,000 children and the incidence of UC from 0.5 to 3.2 per 100,000 children.⁵ The prevalence of IBD in the adult population is approaching 0.3%.⁶ Recently another condition termed “gluten sensitivity” emerged as an important and often underdiagnosed and undertreated disease.^7-11 It is reported that as many as 12% of the healthy population may have serological evidence of gluten sensitivity.⁹ Difficulties in differential diagnosis of those conditions often prompt clinicians to use an exclusion approach by performing tests to rule out the alternative etiologies.² Interestingly, one study shows that most of the celiac disease serological test requests are now from general practitioners rather than gastroenterologists.¹² Another study reports that 72% of general practitioners endorsed IBS as a diagnosis of exclusion.² Endoscopy with biopsies for histological examination remains the gold standard for the diagnosis of many of these conditions.¹³ In recent years, however, introduction of a number of new and improved serological tests may allow for reduction in the number of intestinal biopsies.¹⁴

The cascade includes three testing steps:

Step 1: Celiac Disease Screen: The cascade begins with a celiac screen that includes simultaneous detection of IgA and IgG antibodies to both deamidated gliadin peptide (DGP) and human tissue transglutaminase (tTG). The screen performance is reported to achieve a clinical sensitivity of 98.6% and specificity of 97.0% for the patients with celiac disease or controls.¹⁴ When the result is positive, the testing stops and the interpretive comment on the report would read: “Suggestive of celiac disease or other gluten-sensitive enteropathies.Subsequent testing for ENDOMYSIAL ANTIBODY, IgA (164996) and/or genetic testing for CELIAC DISEASE HLA DQ ASSOCIATION (167082) may be indicated for further patient evaluation." When the result is negative, the testing reflexes to the second step.

Step 2: Inflammatory Bowel Disease Screen: Inflammatory bowel disease screen includes testing for IgG antibodies to anti-Saccharomyces cerevisiae (ASCA), and atypical perinuclear antineutrophil cytoplasmic antibodies (pANCA). This profile of tests aids in the serological identification of patients with IBD and in differentiation among its three clinical forms: CD, UC, and indeterminate colitis. When the marker for CD (ASCA IgG) is positive, the clinical sensitivity for CD is reported to be as high as 74.4% and specificity for IBD as high as 94.4%.¹⁵ When atypical pANCA (a marker of UC) is positive, the clinical sensitivity for UC is reported to be as high as 70% and specificity as high as 80%.¹⁶ It must be emphasized that neither of the markers negatively rules out IBD. Similarly, the presence of these antibodies does not strictly confirm the diagnosis of IBD.¹⁷ Testing for step two is described below and (depending on the combination of results) the interpretive comment on the report would be one of the following: When ASCA IgG is positive and atypical pANCA is negative, testing stops and the comment would read:"Suggestive of Crohn's disease. Subsequent testing with the CROHN'S DISEASE PROGNOSTIC PROFILE (162020) that includes antiglycanantibodies AMCA, ALCA, ACCA, and gASCA (162020) may aid in the differentiation of clinical forms of CD and prognosis ofdisease progression." When ASCA IgG is negative or equivocal and atypical pANCA is positive testing stops and the comment would read: "Suggestive of ulcerative colitis." When both, ASCA IgG and atypical pANCA, are positive testing stops and the comment would read: "Suggestive of IBD. Subsequent testing with the CROHN'S DISEASE PROGNOSTIC PROFILE (162020) that includes antiglycan antibodies AMCA, ALCA, ACCA, AND gASCA may aid in the differentiation of clinical forms of IBD and prognosis of disease progres- sion." When all results are negative then the testing reflexes to the third step.

Step 3: Nonceliac Gluten Sensitivity Screen: The nonceliac gluten sensitivity screen includes testing for IgG antibodies to gliadin with reported clinical sensitivity as high as 87% (for untreated clinically defined celiac disease patients) and specificity as high as 91%.¹⁸ Recent reports show that there is a significant subset of patients who have normal histology for celiac disease, negative for antibodies to DGP and tTG, positive for antigliadin antibodies and clinically indistinguishable from those with celiac disease. Those patients constitute the so-called “nonceliac gluten sensitivity” group, and many of them will benefit from a gluten-free diet. This group of patients is also reported to have increased mortality.^7,8-10,14 When the result is positive, the testing stops and the interpretive comment on the report would read: “Suggestive of nonceliac gluten sensitivity. The patient may benefit from a gluten-free diet.” When all results are negative, the testing stops and the interpretive comment on the report would read: “Suggestive of irritable bowel syndrome (IBS). Careful evaluation of the patient's history, physical examination, and application of Rome III diagnostic criteria may help to rule in or rule out the diagnosis of IBS. Subsequent testing for FECAL CALPROTECTIN (123255) may be recommended. If IBD is strongly suspected, subsequent testing with the CROHN'S DISEASE PROGNOSTIC PROFILE (162020) that includes antiglycan antibodies AMCA, ALCA, ACCA, and gASCA may aid in differential diagnosis." Results of this profile should be used in conjunction with clinical findings and other laboratory tests. 

1. Rubin G, De Wit N, Meineche-Schmidt V, Seifert B, Hall N, Hungin P. The diagnosis of IBS in primary care: Consensus development using nominal group technique. Fam Pract. 2006 Dec, 23(6):687-692. PubMed 17062586

2. Spiegel BM. Do physicians follow evidence-based guidelines in the diagnostic work-up of IBS? Nat Clin Pract Gastroenterol Hepatol. 2007Jun; 4(6):296-297. PubMed 17541444

3. World Gastroenterology Organization Global Guideline, Irritable Bowel Syndrome: A Global Perspective. April 20, 2009.

4. Ce