Celiac Disease

correspondence

Celiac Disease To the Editor: In their review article on celiac disease, Green and Cellier (Oct. 25 issue)1 state that dietary nonadherence is the most common cause of unresponsive celiac disease. Several psychological disturbances — in particular, depression — are associated with celiac disease.2-4 Previous studies have shown that depression is one of the reasons for nonadherence to medical treatment among patients with chronic diseases.5 Since depression is often present in patients with celiac disease both before diagnosis and after a glutenfree diet is recommended,3 nonadherence to a gluten-free diet could be partly due to depressive symptoms. Accordingly, we showed that counseling to provide psychological support can improve adherence to a gluten-free diet and reduce depression in patients with celiac disease.6 The gluten-free diet is the most important treatment for celiac disease. Consequently, it might be helpful to determine whether depression is present in these patients, both at diagnosis and during follow-up. Identification of depression in these patients and subsequent therapy to provide psychological support may increase adherence to a gluten-free diet and reduce complications and possible related hidden costs.6 Cristina D’Angelo, M.D. Antonio Mirijello, M.D. Giovanni Addolorato, M.D. Catholic University of Rome 00168 Rome, Italy 1. Green PHR, Cellier C. Celiac disease. N Engl J Med 2007;

357:1731-43. 2. Addolorato G, Stefanini GF, Capristo E, Caputo F, Gasbarrini A, Gasbarrini G. Anxiety and depression in adult untreated celiac subjects and in patients affected by inflammatory bowel disease: a personality “trait” or a reactive illness? Hepatogastroenterology 1996;43:1513-7. 3. Addolorato G, Capristo E, Ghittoni G, et al. Anxiety but not depression decreases in coeliac patients after one-year gluten-free diet: a longitudinal study. Scand J Gastroenterol 2001;36:502-6. 4. Ludvigsson JF, Reutfors J, Osby U, Ekbom A, Montgomery SM. Coeliac disease and risk of mood disorders — a general population-based cohort study. J Affect Disord 2007;99:117-26. 5. DiMatteo MR, Lepper HS, Croghan TW. Depression is a risk factor for noncompliance with medical treatment: meta-analysis of the effects of anxiety and depression on patient adherence. Arch Intern Med 2000;160:2101-7. 6. Addolorato G, De Lorenzi G, Abenavoli L, Leggio L, Capristo E, Gasbarrini G. Psychological support counselling improves gluten-free diet compliance in coeliac patients with affective disorders. Aliment Pharmacol Ther 2004;20:777-82.

of celiac disease. Patients with otherwise unexplained abnormalities in results of liver-function tests or apparent liver disease alone or in conjunction with other conditions should be screened for celiac disease. Effective exclusion of gluten from the diet can normalize the results of liver-function tests and might even be lifesaving.1 Douglas M. Levin, M.D. Ohio State University Columbus, OH 43210 [email protected] 1. Kaukinen K, Halme L, Collin P, et al. Celiac disease in pa-

tients with severe liver disease: gluten-free diet may reverse hepatic failure. Gastroenterology 2002;122:881-8.

To the Editor: In their review article, Green and Cellier do not discuss two important issues. First, it has been shown that an impaired distribution of intraepithelial natural killer cells induces permanent loss of tolerance to gliadin1 and that a deficiency of natural killer cells permits the development of celiac disease through the loss of normal down-regulation of gut-associated lymphoid tissue by gluten.2 Therefore, all attempts to understand the pathophysiological process of this disease are incomplete without considering the important role of natural killer cells. Second, 99.8% of patients who are positive for all antibodies tested (IgA tissue transglutaminase, IgA endomysial, and IgA and IgG gliadin antibodies) have abnormal (Marsh type 3a, 3b, or 3c) intestinal mucosa.3,4 This constellation has high positive predictive value and, in my view, abrogates the necessity of performing a small-bowel biopsy. Testing for the presence of IgG and especially IgA gliadin antibodies increases the diagnostic significance of testing for IgA tissue transglutaminase and endomysial antibodies. Performing routine serologic tests (assessment only of IgA endomysial and tissue transglutaminase antibodies), as suggested by the authors, would result in the need for more patients to undergo biopsies. In contrast, if used properly, expanded serologic testing might decrease the rate of endoscopic interventions (Fig. 1) and improve the quality of life of patients. Faruk Hadziselimovic, M.D. Annamarie Bürgin-Wolff, Ph.D. Institute for Diagnosing Celiac Disease 4410 Liestal, Switzerland

To the Editor: Green and Cellier do not adequately discuss liver disease as a direct consequence

1. Hadziselimovic F, Emmons R, Schaub U, Signer E, Bürgin-

Wolff A, Krsktic R. Occurrence of large granular lymphocytes

n engl j med 358;7 www.nejm.org february 14, 2008

Downloaded from www.nejm.org at BIBLIOTECA TECNICO SCIENTIF on February 15, 2008 . Copyright © 2008 Massachusetts Medical Society. All rights reserved.

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The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Atypical symptoms

Classic symptoms

Risk factors

Test for total IgA, IgA TTG and endomysial, IgG, and IgA gliadin antibodies

All negative

All positive

Not all positive

No biopsy

No biopsy

Small-bowel biopsy

No celiac disease

Celiac disease, gluten-free diet

Negative findings

Positive findings

Potential celiac disease

Celiac disease, gluten-free diet

Figure 1. Algorithm for Diagnosing Celiac Disease. The titers of total IgA antibodies should be normalGreen for the patient’s age; RETAKE if the total1st level of IgA antibodies is low, AUTHOR: ICM 2nd antibodies is positive, a biIgG tissue transglutaminase (TTG) antibodies should be tested. If the test for IgG TTG REG F FIGURE: 1 of 1 opsy should be performed. If only IgG gliadin antibodies are present, there is little 3rd evidence of celiac disease. The CASE Revised patient should be observed, and the tests should be repeated is performed. Clinical remission after Line before 4-Ca biopsy SIZE EMail ARTIST: ts of celiac adherence to a gliadin-free diet is additional evidence H/T disease. H/T Enon

Combo

33p9

AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset.

and natural killer cells in the epithelium of the gut distinguishPlease check carefully. considered to contribute to underachievement in es two different coeliac diseases. Gut 1992;33:767-72. 1 At the other end of the age spectrum, adulthood. 2. Grose RH, Cummins AG, Thompson FM. Deficiency of inJOB: 35807 ISSUE: 02-14-08 variant natural killer T cells in coeliac disease. Gut 2007;56: cognitive impairment that improves with gluten 790-5. withdrawal2 and dementia3 occur in patients with 3. Bürgin-Wolff A, Hadziselimovic F. Screening test for coeliac celiac disease. The effect of a diagnosis of celiac disease. Lancet 1997;349:1843-4. 4. Bürgin-Wolff A, Gaze H, Hadziselimovic F, et al. Antigliadin disease and appropriate therapy with a gluten-free and antiendomysium antibody determination for coeliac disease. diet need to be explored in a wide spectrum of Arch Dis Child 1991;66:941-7.

The Authors Reply: With regard to the comments by D’Angelo and colleagues, psychological associations with celiac disease, especially depression, are well established and should be addressed as important factors in dietary adherence. Behavioral problems and depression in children and adolescents with undiagnosed celiac disease have been 748

psychological disorders. In view of the association of liver disease and celiac disease, as pointed out by Levin, patients with a variety of liver diseases who are undergoing endoscopy should undergo a duodenal biopsy to exclude celiac disease, irrespective of the results of serologic tests. Hadziselimovic and Buergin-Wolff raise two issues. First, natural killer cells have a role in the



correspondence

pathogenesis of celiac disease. In our review, we describe how intraepithelial lymphocytes in the intestinal mucosa of patients with celiac disease acquire properties of natural killer cells. Second, they propose a protocol to decrease the use of biopsies in the diagnosis of celiac disease. This is a worthy goal; however, serologic tests are neither 100% sensitive nor 100% specific. Although there are problems with biopsies, which include patchiness in the degree of villous atrophy, poor orientation of the biopsy specimen, and variability in the pathological interpretation of villous atrophy, biopsy is currently the diagnostic standard for celiac disease. In addition, at least for adults, a baseline biopsy specimen is important for comparison with follow-up biopsy specimens obtained during dietary treatment, in the case of patients who do not have an optimal response to the gluten-free diet. In the review, we did not mention that two therapeutic approaches to celiac disease are currently being tested in phase 2, placebo-controlled trials (see www.ClinicalTrials.gov). CCX282-B, a CCR9 and leukocyte-migration inhibitor,4 is currently being studied in Finland. In addition, in proof-of-concept studies, AT-1001, an inhibitor of epithelial-barrier dysfunction that has been proved safe and tolerable in patients with celiac disease,

has shown efficacy in blocking signs of gluten toxicity.5 A phase 2b clinical trial of AT-1001 is currently under way in the United States. Investigational drugs in clinical development are a needed response to the unmet medical, social, and economic needs of patients with celiac disease. Peter H.R. Green, M.D. Columbia University College of Physicians and Surgeons New York, NY 10032 [email protected]

Christophe Cellier, M.D., Ph.D. European Georges Pompidou Hospital Paris 75015, France 1. Verkasalo MA, Raitakari OT, Viikari J, Marniemi J, Savilahti

E. Undiagnosed silent coeliac disease: a risk for underachievement? Scand J Gastroenterol 2005;40:1407-12. 2. Hu WT, Murray JA, Greenaway MC, Parisi JE, Josephs KA. Cognitive impairment and celiac disease. Arch Neurol 2006; 63:1440-6. 3. Collin P, Pirttilä T, Nurmikko T, Somer H, Erilä T, Keyriläinen O. Celiac disease, brain atrophy, and dementia. Neurology 1991;41:372-5. 4. Papadakis KA, Prehn J, Moreno ST, et al. CCR9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic Crohn’s disease. Gastroenterology 2001;121: 246-54. 5. Paterson BM, Lammers KM, Arrieta MC, Fasano A, Meddings JB. The safety, tolerance, pharmacokinetic and pharmacodynamic effects of single doses of AT-1001 in coeliac disease subjects: a proof of concept study. Aliment Pharmacol Ther 2007;26:757-66.

Chest-Tube Insertion To the Editor: In the video on chest-tube insertion, Dev et al. (Oct. 11 issue)1 note that chest tubes are generally marked with numbers to indicate the distance into the chest wall. However, this is not the case with the chest tube shown in the video or with models I have used. The centimeter markings shown refer to the distance from the most proximal side hole. Thus, the 2-cm marking lies approximately 4.5 cm from the tip on a 12-French chest tube and 6 cm from the tip on a 20-French tube of the same brand. This subtle difference is particularly important in small neonates, in whom the optimal insertion length may be less than 5 cm. Such patients are thus at risk for chest-tube impingement on the mediastinum, with potential phrenic-nerve injury and diaphragmatic paralysis.2-5 A more intuitive marking system — for example, with the use of “0 cm” (at the proximal hole),

“tip + 2 cm,” “+ 4 cm,” “+ 6 cm,” and so on — along with brief instructions on the package might help practitioners minimize the excessive depth of chest-tube insertion. Joaquim M.B. Pinheiro, M.D., M.P.H. Albany Medical Center Albany, NY 12208 [email protected] 1. Dev SP, Nascimiento B Jr, Simone C, Chien V. Chest-tube

insertion. N Engl J Med 2007;357:e15 (Web only). (Available at http://content.nejm.org/cgi/content/short/357/15/e15.) 2. Arya H, Williams J, Ponsford SN, Bissenden JG. Neonatal diaphragmatic paralysis caused by chest drains. Arch Dis Child 1991;66:441-2. 3. Nahum E, Ben-Ari J, Schonfeld T, Horev G. Acute diaphragmatic paralysis caused by chest-tube trauma to phrenic nerve. Pediatr Radiol 2001;31:444-6. 4. Odita JC, Khan AS, Dincsoy M, Kayyali M, Masoud A, Ammari A. Neonatal phrenic nerve paralysis resulting from intercostal drainage of pneumothorax. Pediatr Radiol 1992;22:379-81. 5. Philipps AF, Rowe JC, Raye JR. Acute diaphragmatic paralysis after chest tube placement in a neonate. AJR Am J Roentgenol 1981;136:824-5.



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