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January 2010

Editor:
Michael Bissell, MD, PhD, MPH

Endomysial antibody test results in celiac disease Endomysial antibody test results in celiac disease

The development and broader application of serologic testing has dramatically altered the medical community’s perception of celiac disease. Celiac disease traditionally has been considered a rare disorder, estimated to occur in approximately one person out of 4,500 in the United States. However, population screening studies have revealed that celiac disease is common, with a prevalence reaching one percent in North American and European populations. Serologic testing plays an increasingly critical role in identifying patients with the disease. Clinical guidelines report that serologic testing for celiac disease can play a major role in improving recognition of at-risk groups. But because serologic tests are not a perfect tool, intestinal biopsy remains the gold standard for diagnosing the disease. None­the­less, clinical guidelines are seldom translated into routine daily practice. Given the difficulty of improving physician practice patterns, coupled with the general lack of awareness about celiac disease among clinicians and frequent reports of delayed and failed diagnoses, serologic testing for celiac disease may not be used optimally. The authors conducted a study to evaluate how positive IgA-endomysial antibody (EMA) test results for celiac disease were being interpreted and addressed by physicians. The authors reviewed consecutive EMA test results, with or without a serum IgA, obtained during a 17-month period. Seropositive tests were cross-referenced to the surgical database to determine the number of patients who underwent intestinal biopsy and the results of the biopsy. The authors sent questionnaires to the ordering physicians of positive tests with no record of intestinal biopsy. They found that among 11,716 EMA tests in 9,533 patients, 349 results were positive in 313 patients. Intestinal biopsies were performed in 218 of the seropositive patients; 194 of them were diagnostic of celiac disease. Celiac disease was also found in 10 EMA-negative patients. Of the 109 positive tests performed in 95 patients with no subsequent biopsy, 28 had appropriate indications to not perform a biopsy, the most common reason being that the test had been ordered as a followup on a previous biopsy-proven diagnosis of celiac disease (n=21). For 33 other positive test results without a subsequent biopsy, management appeared to be inappropriate, most commonly (n=21) because of a recommendation to follow a gluten-free diet despite lack of a tissue diagnosis of celiac disease. For the remaining 48 positive EMA results, either administrative issues prevented evaluation (n=19), the patients refused further evaluation (n=11), or physician surveys were not returned (n=18). The authors concluded that celiac disease affected two percent of patients, with a similar prevalence in male and female patients. Seventy-seven percent of positive EMA tests were managed appropriately by physicians. Beginning a gluten-free diet without biopsy or failing to follow up on a positive EMA test are common management errors.

McGowan KE, Lyon ME, Loken SD, et al. Celiac disease: Are endomysial antibody test results being used appropriately? Clin Chem. 2007;53(10):1775–1781.

Correspondence: J. Decker Butzner at butzner@ucalgary.ca

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Pediatric reference ranges for thyroglobulin Pediatric reference ranges for thyroglobulin

Thyroglobulin is a 660,000 DA glycoprotein composed of two identical, noncovalently linked subunits synthesized by follicular thyroid cells. Under physiological conditions, thyrotropin (thyroid-stimulating hormone [TSH]) primarily regulates thyroglobulin (Tg) production through cyclic adenosine monophosphate (cAMP) as a second messenger. Tg works as a protein scaffold for thyroxine and 3,5,3’-triiodothyronine biosynthesis. Circulating Tg consists of a heterogeneous population of different isoforms as a result of alternative splicing of its mRNA and differences in glycosylation. In the circulation, Tg is first cleared in the liver with an approximate 65-hour half-life. A physiological rise in Tg has been reported for newborns and in maternal serum during the third trimester of pregnancy. A variety of methods are available to measure serum Tg. Nevertheless, even with the most sensitive assays, the clinical value and reliability of serum Tg measurement have limitations due to variability in the specificity of the antibodies used, differences in method standardization, scarce intra- and inter­assay precision, insufficient sensitivity, and the presence of heterophilic or Tg autoantibodies. Yet serum Tg measurement is a useful tool to diagnose and follow up several thyroid disorders. Tg evaluation, along with imaging studies, is a powerful tool for the etiologic diagnosis of congenital hypothyroidism and for elucidating the molecular disturbance involved. But few studies reporting Tg reference ranges measured by current methods are available for the first months of life. The authors conducted a study in which they measured serum Tg in 228 healthy children (110 females and 118 males) aged three to 180 days of life presenting normal age-related serum thyrotropin values and negative anti-Tg and antithyroperoxidase antibodies. Serum Tg was measured by radioimmunoassay (two methods) and immunometric assay (three methods). Mean Tg values measured by the five methods exhibited among-method biases, although a significant positive correlation was observed. Serum Tg levels measured by the five methods showed a correlation with age but not with TSH or gender. During the first days of life, relatively high mean Tg levels were observed, which progressively decreased until they reached a plateau. Therefore, with the aim of establishing reference values, the population was separated into two age groups: from three to 15 days of life (group A) and from 16 to 180 days of life (group B). The authors found that the mean Tg concentration in group A was statistically higher than in group B. Tg centile distributions were calculated to establish the normal levels of serum Tg for each method. The authors concluded that for a correct interpretation of serum Tg levels, age and methods used should be considered.

Sobrero G, Munoz L, Bazzara L, et al. Thyroglobulin reference values in a pediatric infant population. Thyroid. 2007;17(11): 1049–1054.

Correspondence: Gabriela Sobrero at gmsobrero@gmail.com

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HPV-associated IFN-<em>y</em> assay as a predictor of ­surgical outcome HPV-associated IFN-y assay as a predictor of ­surgical outcome

Cervical cancer is the second most common cancer in women worldwide and results from persistent infection with human papillomaviruses. Development of HPV-related neoplastic lesions, from cervical intraepithelial neoplasia (CIN) to cervical carcinoma, is due to infection by high-risk human papillomavirus (HPV) genotypes in which integration of the viral episome into host-cell DNA occurs. The oncogenic effects are mediated by the viral early proteins E6 and E7 binding to the products of the tumor suppressor genes p53 and retinoblastoma, respectively. The immune system plays an important role in controlling HPV infections. Immunosuppressed women have an increased incidence of HPV infections, CIN lesions, and prolonged persistence of intraepithelial lesions. Abs against HPV proteins can be found in the sera of patients, and regressing lesions are infiltrated by immune cells. Although development of HPV-derived tumors has been related to immune escape mechanisms, little is known about the role of T-cell immunity against HPV in the different stages of disease progression. Even less is known about the ability to induce immune responses among the various high-risk HPV genotypes. Studies primarily have focused on HPV-16 because it is the most common genotype found in neoplastic lesions. HPV-18 is the second most common incident HPV infection and the infection most strongly associated with adenocarcinoma of the cervix. Previous studies involving healthy subjects have shown high frequencies of circulating memory CD4+ T cells reacting with HPV-16 E2 and E6, but not E7, sequences. Much less is known about HPV-18. The authors investigated the presence and quality of anti-HPV-18 E6 CD4+ T-cell responses in the blood of 37 consecutive patients with high-grade cervical lesions, 25 normal donors, and 20 cord blood collections. They also evaluated the immune infiltrate in the cervical lesions. The characteristics of the responses were correlated to clinical outcome. The authors found that one or more HPV-18 E6 peptides, containing naturally processed epitopes, could induce a response in 40 to 50 percent of patients, depending on the effector function tested. These percentages rose to 80 to 100 percent when HPV-18-positive patients were considered. HPV-18 E6-specific CD4+ T cells produced mixed Th1/Th2 responses. Statistical analysis of the cytokines produced revealed that the amount of IFN-y released could predict persistence of infection or disease relapse after surgery, or both. The authors also found that a higher number of infiltrating CD4+ and T-bet+ T cells in the lesions correlated with a favorable clinical outcome. The authors concluded that the results strongly suggest a relevant role for CD4+ T cells in controlling HPV-18 compared with HPV-16 infections in patients with high-grade cervical lesions. They also identify an immunologic parameter that may be useful for stratifying patients.

Seresini S, Origoni M, Lillo F, et al. IFN-y produced by human papilloma virus-18 E6-specific CD4+ T cells predicts the clinical outcome after surgery in patients with high-grade cervical lesions. J Immunol. 2007;179:7176–7183.

Correspondence: Dr. Maria Pia Protti at mprotti@hsr.it

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Clinical pathology abstracts editor: Michael Bissell, MD, PhD, MPH, professor, Department of Pathology, Ohio State University, Columbus.