Celiac Disease (Sprue) Workup
- Author: Stephan U Goebel, MD; Chief Editor: BS Anand, MD more...
The diagnosis of celiac disease is confirmed via histopathologic evaluation of duodenal biopsy specimens. Controversy exists regarding making the diagnosis without biopsy in specific cases, particularly in the pediatric population.
In 2013, The American College of Gastroenterology (ACG) issued clinical guidelines regarding the diagnosis and treatment of celiac disease, including the following[2, 3] :
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
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
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. 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%.
Patients with diabetes mellitus type 1, Down syndrome, or Turner syndrome have an increased incidence of celiac disease.
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.
Anemia due to deficiency in iron, folate, and, rarely, vitamin B-12 might be present. A low serum iron level is common.
The prothrombin time (PT) might be prolonged because of malabsorption of vitamin K.
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.
The most sensitive and specific antibodies for the confirmation of celiac disease are tissue transglutaminase IgA, 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 either were elderly or had severe disease.
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. 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.
The authors developed a series of diagnostic algorithms to compare costs and resource utilization. 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.
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.
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.
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).
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
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