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Celiac Disease (Sprue) Workup

  • Author: Stephan U Goebel, MD; Chief Editor: BS Anand, MD  more...
Updated: Nov 20, 2015

Approach Considerations

The diagnosis of celiac disease is confirmed via histopathologic evaluation of duodenal biopsy specimens.[7] 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, 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.[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]


Laboratory Studies

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.

Hematologic tests

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.

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.


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

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.



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).



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
Contributor Information and Disclosures

Stephan U Goebel, MD Assistant Professor of Gastroenterology and Hepatology, Department of Medicine, Emory University School of Medicine

Stephan U Goebel, MD is a member of the following medical societies: American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.


James L Achord, MD Professor Emeritus, Department of Medicine, Division of Digestive Diseases, University of Mississippi School of Medicine

James L Achord, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Medical Association, American Society for Gastrointestinal Endoscopy, Mississippi State Medical Association, New York Academy of Sciences, Sigma Xi, and Southern Medical Association

Disclosure: Nothing to disclose.

Mounzer Al Samman, MD Assistant Professor, Department of Internal Medicine, Division of Gastroenterology, Texas Tech University School of Medicine

Mounzer Al Al Samman, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, and American Gastroenterological Association

Disclosure: Nothing to disclose.

Jan-Michael A Klapproth, MD Assistant Professor, Department of Medicine, Division of Digestive Diseases, Emory University School of Medicine

Jan-Michael A Klapproth, MD is a member of the following medical societies: American College of Gastroenterology, American Federation for Medical Research, American Gastroenterological Association, and Crohns and Colitis Foundation of America

Disclosure: Nothing to disclose.

Vincent W Yang, MD, PhD R Bruce Logue Professor, Director, Division of Digestive Diseases, Department of Medicine, Professor of Hematology and Oncology, Winship Cancer Institute, Emory University School of Medicine

Vincent W Yang, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Gastroenterological Association, American Society for Clinical Investigation, and Association of American Physicians

Disclosure: Nothing to disclose.

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