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Can Tissue Transglutaminase Antibody Titers Replace Small-Bowel Biopsy to Diagnose Celiac Disease in Select Pediatric Populations?

Collin C. Barker, MD^*, Craig Mitton, PhD, Gareth Jevon, MD and Thomas Mock, PhD^||

^* Department of Pediatrics
Department of Health Care and Epidemiology
Department of Pathology
^|| Department of Pathology and Laboratory Medicine, British Columbia Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
Objectives. The use of screening tests for celiac disease has increased the number of patients referred for evaluation. We proposed that the subgroup of patients with very high tissue transglutaminase antibody (TTG) titers is positive for celiac disease and a small-bowel biopsy is not necessary to make the diagnosis. A gluten-free diet should be attempted and, if the patient’s symptoms do not improve, then a biopsy should be performed to confirm the diagnosis.

Methods. A chart review of data for 103 patients who underwent both TTG testing and a small-bowel biopsy was performed. We examined the impact of using TTG values of >100 U and <20 U as cutoff values and suggested performing biopsies for patients with TTG values of 20 to 100 U, as is current practice.

Results. Fifty-eight of 103 patients demonstrated positive biopsy results. Forty-nine of 103 patients had TTG levels of >100 U, with 48 of 49 exhibiting positive biopsy results. Only 7 of 16 patients with TTG values of 20 to 100 U exhibited positive biopsy results. Three patients with TTG levels of <20 U had positive biopsies; 2 were IgA negative and 1 had a duodenal ulcer. With the cutoff values of >100 U and <20 U with known IgA status, the sensitivity was 0.980 (48 of 49 cases) and the specificity was 0.972 (35 of 36 cases). An incremental cost analysis found that this proposal could potentially decrease the costs of investigation and diagnosis by almost 30%.

Conclusions. When the cutoff values were changed to >100 and <20 U and IgA levels were verified, the sensitivity and specificity were very high. Patients with mid-range TTG values (20–100 U) or values of <20 U with negative IgA status should continue to undergo biopsies for diagnosis of celiac disease.

Key Words: tissue transglutaminase antibody • celiac disease • biopsy

Abbreviations: TTG, tissue transglutaminase antibody • EGD, esophagogastroduodenoscopy • IDDM, insulin-dependent diabetes mellitus

Celiac disease is the most common cause of malabsorption in western nations, with an estimated prevalence of 1 case per 99 to 250 population.^1,2 The increasingly widespread use of screening tests for celiac disease has raised awareness and increased the number of patients referred for evaluation. It is recognized that celiac disease occurs with a greater prevalence (2–10%) in association with insulin-dependent diabetes mellitus (IDDM), other autoimmune diseases, Down syndrome, Turner’s syndrome, and a family history of celiac disease.^3–13 For symptomatic patients, typical clinical findings include failure to thrive, short stature, delayed puberty, anorexia, abdominal distention, diarrhea, and abdominal discomfort. Laboratory findings may include iron-deficiency anemia, low levels of albumin, calcium, potassium, sodium, and folate, increased alkaline phosphatase levels and prothrombin time, and steatorrhea. However, most patients identified with screening tests have few or no symptoms of celiac disease.^1,2

The current standard method for diagnosis of celiac disease is an adequate small-bowel biopsy (usually obtained through upper gastrointestinal tract endoscopy) showing characteristic histopathologic changes (categorized with the modified Marsh criteria¹⁴), followed by a therapeutic response to a gluten-free diet.¹⁵ Since Dieterich et al^16,17 first identified transglutaminase as the autoantibody in celiac disease and found it to be predictive of the disease, assays have been developed to screen for it.^18,19 Commercially available IgA tissue transglutaminase antibody (TTG) screening tests have been developed with sensitivities and specificities in the 93% to 97% range, with the manufacturer-recommended cutoff values.²⁰ Because these are screening tests, the cutoff values are designed to optimize the sensitivity of the test so that all potentially positive cases are identified. The use of higher-titer cutoff values than currently recommended should improve the specificity of the test and its positive predictive value.

We propose that the subgroup of patients with very high TTG titers are positive for celiac disease and that a small-bowel biopsy is not necessary for diagnosis for this select group. A gluten-free diet should be tried and, if the patient’s symptoms do not improve, then a biopsy should be performed to confirm the diagnosis. A cost analysis comparing the current practice of endoscopy with biopsy for all patients with selective endoscopy based on TTG titers is also outlined.

	METHODS

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Study Design
We performed a retrospective chart review of data for 103 patients who had undergone both TTG testing and a small-bowel biopsy at British Columbia Children’s Hospital between September 2000 and October 2003. A search for predispositions to celiac disease included IDDM, thyroid disease, Down syndrome, Addison’s disease, Turner’s syndrome, alopecia areata, premature puberty, cystic fibrosis, and autism. Family history was examined for any autoimmune disease and specifically celiac disease among first-degree relatives. IgA deficiency was recorded, to ensure the validity of the IgA-based TTG results. The biopsies were reviewed by a pathologist blinded to the patients’ clinical history, TTG results, and previous biopsy reports. Reporting was based on the modified Marsh criteria.¹⁴ A modified Marsh grade of 2 was reported as positive.

The 2 commercial TTG kits used by our hospital laboratory during the examination period were Quanta Lite human tTG IgA, used from June 2002 to October 2003, and Quanta Lite guinea pig tTG IgA (INOVA Diagnostics, San Diego, CA), used before June 2002. The manufacturers’ recommended TTG cutoff values, which were validated previously by the hospital laboratory, were <20 U for negative and 20 U for positive. Our laboratory reports individual values from 1 to 100 U and >100 U. We used TTG levels of >100 U and <20 U for proposed cutoff values for diagnosis and suggested performing biopsies for patients with TTG values of 20 to 100 U (as is current practice).

The potential cost difference for these investigations can be assessed by examining either average or incremental costs. An average cost is simply the cost per 1 unit of output, whereas the incremental (or marginal) cost is the cost associated with producing I unit more or 1 unit less of output.²¹ The calculation of the total average cost is the sum of all costs related to a given procedure (ie, personnel, consumable materials, tests, capital equipment, and buildings) divided by the total output (ie, number of patients treated or number of procedures performed). Calculation of the incremental cost involved only the identified components that changed when 1 more or 1 less procedure was performed. For examination of the costs of interventions to determine the best utilization of limited health care resources, it is appropriate to base analyses on incremental costs.²¹ This is because, unless there is a change in the number of procedures that produces reallocation of substantive amounts from the savings incurred (through personnel changes or the opening or closing of facilities), overhead costs and salaried personnel costs remain unchanged.

In our specific case, the total average cost for endoscopy included nursing support, hospital overhead, pathology costs, and physician fees. In contrast, the incremental cost included only the physician fees, because this was the only cost variable that would be realistically expected to change with the relatively small percentage of endoscopies per year and that would be actually affected by the proposed change in practice. That is, performing several fewer procedures would save with respect to physician billings but would not affect nursing costs or hospital overhead costs. The baseline cost, which was unchanged, included referral to the pediatric gastroenterologist, dietary teaching, and routine, intermittent, follow-up monitoring.

Inclusion and Exclusion Criteria
All consecutive patients treated at the gastroenterology clinic at British Columbia Children’s Hospital who underwent TTG testing through the hospital laboratory before or on the same day as the small-bowel biopsy were included in the study. Patients on a gluten-free diet were excluded from the study. If the TTG level was measured after the biopsy, then the patient was excluded because of the possibility that the gluten-free diet had already been initiated. Incomplete records, with respect to hospital-based TTG results or missing or inadequate pathology slides, excluded 2 patients from the study. This study received ethical approval from the Clinical Review Ethics Board, Office of Research Services, at the University of British Columbia.

Statistical Analyses
Descriptive analysis of the population was performed with summary measures. Comparisons of groups with a predisposition to or family history of celiac disease were made with Fisher’s exact test. The sensitivity and specificity of the TTG test were assessed with the proposed cutoff values outlined previously. Positive and negative predictive values were derived with a range of prevalences for celiac disease in the patient population. Receiver operating characteristic curves were created to compare TTG and biopsy findings.

A cost analysis was performed to compare the newly proposed staged approach with the current standard of care. Stata 8.0 software (Stata Corp, College Station, TX) was used for statistical analyses.

	RESULTS

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Demographic Features, Presenting Symptoms, and Predispositions to Celiac Disease
A total of 58 of 103 patients (14 male patients and 44 female patients) demonstrated positive biopsy results for celiac disease. The remaining 45 patients (24 male patients and 21 female patients) demonstrated negative biopsy results. The average age of the group was 8.69 ± 4.56 years. The ethnic distribution was 89 white (47 positive for celiac disease), 11 East Indian (Punjabi) (9 positive), 1 Native Aboriginal (negative), 1 Afghani (positive), and 1 Turk (positive) (Table 1).

Any predisposition to celiac disease was found for 31 subjects, of whom 22 had positive biopsy results. The most common predispositions (alone or in combination) among biopsy-positive patients included 14 with IDDM, 4 with thyroid disease, and 4 with Down syndrome. IgA deficiency was found for 2. Other autoimmune-associated diseases (Addison’s disease, alopecia areata, and premature puberty) were also represented (1 each) in this cohort. Other potential predisposing associations included Turner’s syndrome, autism, and cystic fibrosis (1 each). Only 6 of 11 patients with a family history of celiac disease in a first-degree relative demonstrated positive biopsy results, as opposed to 12 of 16 patients with a history of autoimmune disease. The positive family histories of nonceliac autoimmune-mediated diseases included thyroid disease (11), IDDM (2), inflammatory bowel disease (2), and multiple sclerosis (2).

Only a minority of patients with biopsy-positive celiac disease had any underlying predisposition for developing it (22 of 58 patients, 38%). This proportion was equivalent to that of the overall sample population (31 of 103 patients, 30%). However, IDDM, hypothyroidism, and Down syndrome were more frequent among patients with biopsy-positive disease and those with TTG levels of >100 U. Only IDDM was noted for a significantly greater proportion of patients with biopsy-proven celiac disease (P = .030).

The proportions of patients with a family history of celiac disease were equal for positive and negative biopsy results. However, a greater proportion of patients with a family history of autoimmune thyroid disease demonstrated positive biopsy findings for celiac disease. Endocrinology referrals represented 23 of 103 patients (22%) in this population, reflecting a referral bias for this population at our institution.

TTG and Biopsy Results
Sixteen patients had TTG values between 20 and 100 U, of whom 7 exhibited positive biopsy results (44%). Three patients with TTG levels of <20 U had positive biopsies. Of these 3 patients, 2 were IgA negative and 1 was IgA sufficient but with a duodenal ulcer of which the blinded pathologist was unaware. The biopsies were obtained near the ulcer site. The original pathologist did not report this patient as positive for celiac disease, only the blinded pathologist did (Table 2). The 1 patient with a TTG level of >100 U and a negative biopsy had cystic fibrosis and a duodenal ulcer. The patient was asymptomatic, and the TTG testing was performed as part of routine screening. The child has remained asymptomatic; the TTG levels have decreased from the original values but remain elevated. Results for the human TTG IgA and guinea pig TTG IgA assays were equivalent overall and when the IgA-insufficient patients and patients with values of 20 to 100 U were removed. Therefore, values were condensed into a single table for ease of depiction of results.

The sensitivity calculated with the new TTG cutoff values of >100 and <20 U, with known IgA status, was 0.980 (48 of 49 cases). The specificity was calculated to be 0.972 (35 of 36 cases) (Table 3). These values, when plotted on a receiver operating characteristic curve, yielded an area under the curve of 0.9567 (Fig 1).

View larger version (11K): [in this window] [in a new window]   Fig 1. Receiver operating characteristic (ROC) curve of sensitivity and 1 – specificity for TTG levels of >100 or <20 U with known IgA sufficiency.

All symptomatic patients with TTG levels of >100 U and positive small-bowel biopsy results exhibited clinical improvement, with respect to their presenting symptoms, on a gluten-free diet if they adhered to the diet. Follow-up TTG testing was not performed routinely to assess whether the values improved. Among the patient records that did have reported follow-up values, all showed decreases from the values at presentation if the patients adhered to their gluten-free diets.

Cost Analysis
Sixty-five patients had "positive" TTG test results (>20 U) during the 2.83-year study period. This equates to 23 esophagogastroduodenoscopies (EGDs) per year specifically to investigate for celiac disease. If the proposed cutoff values had been instituted, 49 EGDs could had been avoided during the study period or 17 EGDs per year.

The baseline cost for assessment, investigation, and dietary counseling without EGD is $490.00 per patient. This cost would not change whether or not an EGD was performed.

The incremental cost of each additional EGD is $347.00 (average cost is $1092.00) (Table 4). The incremental cost savings with the proposed cutoff values would be the costs associated with not performing 17 EGDs per year, or $5899.00 ($347.00 x 17). The new annual cost of investigation for celiac disease at our institution would be the cost of 23 assessments (at $490.00 per patient) plus the cost of 23 EGDs (at $347.00 per patient) minus the incremental cost of 17 EGDs (at $347.00 per patient). This works out numerically to be $19 251.00 – $5899.00 = $13 352.00. The incremental cost saving with no EGD for patients with TTG levels of >100 U equates to 31%. If 1 patient needs to be reevaluated and investigated with an EGD at an incremental cost of $391.00 (clinic visit = $44.00 and EGD = $347.00), then the incremental savings decreases by $391.00 to $5508.00 or 29%.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION REFERENCES

 
The purpose of this preliminary study was to determine whether there is a TTG screening titer at which false-positive results are minimized and celiac disease can be diagnosed accurately, so that intestinal biopsy is no longer required. With the cutoff values for our commercial TTG screening kit changed to >100 U and <20 U and IgA levels checked, the sensitivity and specificity of the TTG screening test were very high (0.980 and 0.972, respectively). Only 1 patient demonstrated incorrectly diagnosed positive results with this screening criterion. The only presenting symptoms in our cohort associated with biopsy-positive celiac disease were failure to thrive and short stature. The only predisposing factor in the proband for a positive biopsy was having IDDM. Of note, 6 patients <2 years of age were diagnosed with TTG testing with biopsy confirmation and response to a gluten-free diet, despite previously reported problems/concerns in this age group.¹⁵

Patients with TTG values between 20 and 100 U or <20 U with negative IgA results should undergo biopsies for conclusive diagnosis (because of the lower diagnostic accuracy of TTG values at these levels). If patients with TTG levels of >100 U do not experience symptomatic improvement with the gluten-free diet, then they should be evaluated with small-bowel biopsies, to ensure accurate diagnoses. Patients with normal TTG results (TTG levels of <20 U) with highly suggestive symptoms or predispositions to celiac disease should also undergo biopsies, to rule out the diagnosis.

This newly proposed stepwise approach to celiac disease appears to be accurate in its ability to diagnose biopsy-positive celiac disease, because of the greater proportions of patients with celiac disease in our tertiary-care center gastroenterology clinic population from endocrinology referrals, higher-risk populations, and symptomatically consistent cases. The positive predictive value is increased, compared with that for a general population sample, because of the referral patterns. This skewed population, which would be considered normally a detriment, is an advantage in enhancing the positive predictive value. Twenty-three of 103 patients were referred from the endocrinology service. Of these 23, 20 demonstrated biopsy-positive celiac disease and 17 had TTG levels of >100 U.

Recently, Scoglio et al²² proposed a pretest probability of up to 75% among patients referred to their clinic on the basis of suspicious gastrointestinal symptoms, nongastrointestinal symptoms, and familial screening for celiac disease. Table 5 displays calculated positive and negative predictive values using more modest assumptions of pretest probability (possible prevalence of the disease in the population) with the measured sensitivity and specificity in our "enriched"/skewed population. When screened, the general population (estimated prevalence of 1 case per 300 population) shows a low positive predictive value but a very high negative predictive value. The positive predictive value increases only when the prevalence of the disease reaches 5%, with reasonable accuracy at >10% (Table 5). We suspect a more-modest estimated pretest prevalence, in the range of 15% to 25%, for our clinic.

Except for IDDM in the proband, a family history of celiac disease, other autoimmune disorders among first-degree relatives, and other risk factors in the proband were not predictive of biopsy-positive celiac disease in this cohort. This was surprising, because of the known associations reported in previous studies.^{3–13,15–20,22–24} However, this might be explained on the basis of some patients who were referred to gastroenterology services for other problems and also underwent TTG testing, performed as part of our prescreening evaluation. These investigations were based on symptoms described in the referral letters.

Each year, a few families attend our clinic who have received positive TTG screening test results and have started their child on a gluten-free diet. If the child is "symptomatically improved," then the family does not wish to reintroduce gluten into the diet for several months to allow a valid small-bowel biopsy to be obtained. These families are seen by our dietitian and are given the same teaching package as are our patients with biopsy-proven disease; they are monitored on an as-needed basis in our clinic, on the basis of patient symptoms. Such patients were not included in this study.

The cost analysis found that this proposal might decrease the expense of investigation and diagnosis of celiac disease among patients by almost 30%. In addition, the delays to instruction and institution of the gluten-free diet would be reduced by weeks. With the potential reallocation of resources and reduction of waiting lists, this would benefit all patients and improve the overall efficiency of the health care system.

The main shortcomings of this proposal would be the potential misdiagnosis of patients as having celiac disease and the possible delay in investigation with EGD for other conditions mimicking celiac disease symptoms or causing positive screening test results. Known causes of falsely positive TTG screening include liver disease and small-bowel inflammation.^23,24 We routinely screen laboratory results for any hepatic abnormalities and, if any competing diagnosis would require EGD, then the procedure is performed as indicated. With respect to misdiagnosis, the proposal has taken into account reassessment and confirmation of the diagnosis if there is no patient improvement. Because the diet is safe and nutritionally appropriate, the possibility of overdiagnosis is not overtly harmful, and the patients can test themselves without the diet in the future, to allow reassessment, if desired.

The IgG TTG test has been known as a research tool since 2000. It has not yet reached widespread clinical use but would be useful for patients with IgA deficiency, to screen them for celiac disease with both high sensitivity and high specificity.^25,26 Once this test gains widespread use, it could be used in conjunction with the IgA TTG test to screen for celiac disease without the need to assess IgA deficiency.

This proposed staged method of investigation could decrease the time to diagnosis by eliminating the need for all patients to undergo biopsy. Through the outlined efficiency gain, resources would be freed for diversion to other areas of the medical system.

Because these data are from a single laboratory, they should be considered preliminary and should be validated in a multicenter study, to confirm their generalizability. We have begun to undertake this step, to determine whether similar results can be attained in other centers across Canada and to ascertain what real savings to the national health care system can be achieved. When this preliminary work is completed, a prospective trial should be performed, to ensure reproducibility of these results. We hope to use this type of approach in other areas, to streamline our investigation profiles, to improve health care delivery, and to identify possible cost savings for the health care system.

	FOOTNOTES

 
Accepted Sep 15, 2004.

Reprint requests to (C.C.B.) Division of Gastroenterology, British Columbia Children’s Hospital, Room K4-180, Vancouver, British Columbia, Canada, V6H 3V4. E-mail: cbarker{at}cw.bc.ca

No conflict of interest declared.

	REFERENCES

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