Correspondence

Celiac Disease

N Engl J Med 2008; 358:747-749February 14, 2008

Article

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 gluten-free 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

6 References

1. 1

   Green PHR, Cellier C. Celiac disease. N Engl J Med 2007;357:1731-1743
   Full Text | Web of Science | Medline

2. 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;43:1513-1517
   Web of Science | Medline

3. 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;36:502-506
   CrossRef | Web of Science | Medline

4. 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;99:117-126
   CrossRef | Web of Science | Medline

5. 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;160:2101-2107
   CrossRef | Web of Science | Medline

6. 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;20:777-782
   CrossRef | Web of Science | Medline

To the Editor:

Green and Cellier do not adequately discuss liver disease as a direct consequence 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
dlevin@cmgastro.com

1 References

1. 1

   Kaukinen K, Halme L, Collin P, et al. Celiac disease in patients with severe liver disease: gluten-free diet may reverse hepatic failure. Gastroenterology 2002;122:881-888
   CrossRef | Web of Science | Medline

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 (Figure 1Figure 1Algorithm for Diagnosing Celiac Disease.) 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

4 References

1. 1

   Hadziselimovic F, Emmons R, Schaub U, Signer E, Burgin-Wolff A, Krsktic R. Occurrence of large granular lymphocytes and natural killer cells in the epithelium of the gut distinguishes two different coeliac diseases. Gut 1992;33:767-772
   CrossRef | Web of Science | Medline

2. 2

   Grose RH, Cummins AG, Thompson FM. Deficiency of invariant natural killer T cells in coeliac disease. Gut 2007;56:790-795
   CrossRef | Web of Science | Medline

3. 3

   Burgin-Wolff A, Hadziselimovic F. Screening test for coeliac disease. Lancet 1997;349:1843-1844
   CrossRef | Web of Science | Medline

4. 4

   Burgin-Wolff A, Gaze H, Hadziselimovic F, et al. Antigliadin and antiendomysium antibody determination for coeliac disease. Arch Dis Child 1991;66:941-947
   CrossRef | Web of Science | Medline

Author/Editor Response

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 considered to contribute to underachievement in adulthood.1 At the other end of the age spectrum, cognitive impairment that improves with gluten withdrawal2 and dementia3 occur in patients with celiac disease. The effect of a diagnosis of celiac disease and appropriate therapy with a gluten-free diet need to be explored in a wide spectrum of 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 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
pg11@columbia.edu

Christophe Cellier, M.D., Ph.D.
European Georges Pompidou Hospital, Paris 75015, France

5 References

1. 1

   Verkasalo MA, Raitakari OT, Viikari J, Marniemi J, Savilahti E. Undiagnosed silent coeliac disease: a risk for underachievement? Scand J Gastroenterol 2005;40:1407-1412
   CrossRef | Web of Science | Medline

2. 2

   Hu WT, Murray JA, Greenaway MC, Parisi JE, Josephs KA. Cognitive impairment and celiac disease. Arch Neurol 2006;63:1440-1446
   CrossRef | Web of Science | Medline

3. 3

   Collin P, Pirttila T, Nurmikko T, Somer H, Erila T, Keyrilainen O. Celiac disease, brain atrophy, and dementia. Neurology 1991;41:372-375
   Web of Science | Medline

4. 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;121:246-254
   CrossRef | Web of Science | Medline

5. 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;26:757-766
   CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   Marie-Nathalie Beaudoin, Philip G. Zimbardo. (2011) A medical issue affecting the diagnosis of mood, attention and autistic disorders: a closer look at celiac disease and gluten sensitivity. Health Psychology Review1-19
   CrossRef

2. 2

   Peter Toftedal, Christian Nielsen, Jonas Trolle Madsen, Kjell Titlestad, Steffen Husby, Søren Thue Lillevang. (2010) Positive predictive value of serological diagnostic measures in celiac disease. Clinical Chemistry and Laboratory Medicine 48:5, 685-691
   CrossRef

3. 3

   V. Malalasekera, F. Cameron, E. Grixti, M. C. Thomas. (2009) Potential reno-protective effects of a gluten-free diet in type 1 diabetes. Diabetologia 52:5, 798-800
   CrossRef

4. 4

   A. Bürgin–Wolff, F. Hadziselimovic. (2008) Two-Step Approach for Diagnosing Celiac Disease. Clinical Gastroenterology and Hepatology 6:10, 1173
   CrossRef