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CLINICAL REVIEW:
Andrew D Hopper, Marios Hadjivassiliou, Sohail Butt, and David S Sanders
Adult coeliac disease
BMJ 2007; 335: 558-562 [Full text]

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Rapid Responses published:

�In vivo� targeting of tissue transglutaminase � a milestone in diagnosing of celiac disease: Petar I Ivanovski, Ivan P. Ivanovski (14 September 2007)

Celiac Disease: The great imitator: Shirwan A. Mirza, MD, FACP, FACE (15 September 2007)

Coeliac disease: rheumatic presentations are common: Alastair L Hepburn (16 September 2007)

British guidelines on necessity of bone densitometry in coeliac disease: Robert J Mead, Moses Duku, Pradeep Bhandari, Suzie Green. (17 September 2007)

Unexplained Anemia.: Mohammad Shaikhani (19 September 2007)

Association between anorexia nervosa and coeliac disease: Luca Mascitelli, Francesca Pezzetta (21 September 2007)

�In vivo� targeting of tissue transglutaminase � a milestone in diagnosing of celiac disease 14 September 2007

Petar I Ivanovski,
pediatrician
University Children`s Hospital Belgrade,
Ivan P. Ivanovski
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Re: �In vivo� targeting of tissue transglutaminase � a milestone in diagnosing of celiac disease

Celiac disease (CD) may affect up to one in a hundred people, only one case in seven is ever diagnosed, and an appreciable diagnostic delay of many years often occurs.1 2 The internationally accepted �gold standard� diagnostic test for CD is the demonstration of villous atrophy on a duodenal biopsy.3 4 Undiagnosed, and consequently untreated celiac disease, is associated with high morbidity and increased mortality.5 6
To advance the diagnostic field, gastroenterologists involved in CD seek for clinical prediction rules in order to optimize the sensitivity and specificity of the diagnostic approach to CD. Recently Hopper and colleagues7 reported a rare accomplishment in this regard. They got a decision rule that achieved 100% sensitivity in detection of CD.
Briefly, Hopper and colleagues had a cohort of 2000 patients, all of whom underwent intestinal biopsy. The patients were divided in two groups, high, and low risk group, according to the presence or absence of clinical signs indicating CD (weight loss, anemia or diarrhea). Each group was further divided into subgroups with positive or negative serology (tissue transglutaminase antibody). Their results are as follows:
- None of the 1170 low risk patients with negative serology was found to have CD. All of them had normal intestinal histology.
- Only six out of 91(6,6%) low risk patients with positive serology was found to have CD! Eightyfive (93,46%) low risk patients with positive serology did not have CD, because they had morphologically normal intestinal mucosa!
- Seven out of 585(1,2%) high risk patients with negative serology had CD, and the rest, 478(98,8%) patients, of this group did not have CD, ie. had normal intestinal histology.
- In high risk, serology positive patients, out of 154, sixty-four (40%) was found to have CD, and 90(60%) high risk patients with positive serology did not have CD, ie. had normal morphology of the intestinal mucosa.
According to Graber and Kumar8 the decision rule of Hopper and colleagues seems to be the most cost effective and efficient way to assess celiac disease, until a better rule is developed and validated. We feel that better rule is already found. Namely, M�ki and colleagues9 recently showed for the first time that in vivo targeting of tissue transglutaminase (tTG) in CD occurs in the form of in situ endomysisal, reticulin and jejunal subepithelial IgA autoantibody binding. Furthermore the authors showed that celiac autoantibodies are deposited in morphologically normal small intestinal mucosa, before they can be detected in the circulation and that the tTG specific IgA deposition precedes the formation of the gluten induced flat jejunal lesions.9
These findings raise the possibility for developing and validating better prediction rule, with the final goal of optimizing the sensitivity and specificity of diagnostic approach to CD.
The time for upgrading the histological criteria currently in use3 4 is coming. Patients with small intestinal morphology consistent with CD histology do have celiac disease. Patients with positive serology regardless of symptomatology, and patients with negative serology but with typical symptoms for CD, if found to have normal small intestine morphology, to be confirmed or excluded of having CD, will have their intestinal samples to be tested for in vivo targeting of tTG in the form of in situ endomysisal, reticulin and jejunal subepithelial IgA autoantibody binding. If �in vivo targeting� is found then the patient does have CD and must be put on gluten free diet.
This approach would be a reasonable way for reaching a milestone in diagnosing of all celiac patients, including clinically pertinent celiac disease patients with normal small-bowel mucosal villous architecture as well.
References:
1. Rostom A, Murray JA, Kagnoff MF. American Gastroenterology Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology 2006;131:1981-2002.
2. Green PHR, Stavropolous SN, Panagi SG, Goldstein SL, McMahon DJ, Absan H, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastro 2001;96:126-31.
3. Revised criteria for diagnosis of celiac disease. Report of working group of European Society of Pediatric Gastroenterology and Nutrition. Arch Dis Child 1990;65:909-11.
4. National Institutes of Health Consensus Development Conference Statement on Celiac Disease, June 28-39, 2004. Gastroenterology 2005;128(4 suppl):S1-9.
5. Logan RF. Rifkind EA, Turner ID, Ferguson A. Mortality in celiac disease. Gastroenterology 1989;97:265-71.
6. West J, Logan RF, Smith CJ, Hubbard RB, Card TR. Malignancy and mortality in people with celiac disease: population based cohort study. BMJ 2004;329:716-9.
7. Hopper AD, Dixon S, Huristone DP, Cross SS, McAlindon ME, Lobo AJ, et al. Pre-endoscopy serological testing for celiac disease: evaluation of a clinical decision tool. BMJ 2007;334:729-32.
8. Graber ML, Kumar A. Commentary: Reaching a milestone in diagnosing celiac disease. BMJ 2007,334:732-3.
9. Korponay-Szab� IR, Halttunen T, Szalai Z, Laurila K, Kir�ly R, Kov�cs JB, F�s�s L, M�ki M. In vivo targeting of intestinal and extraintestinal transglutaminase 2 by celiac autoantibodies. Gut 2004;53:641-8.
Competing interests: None declared

Celiac Disease: The great imitator 15 September 2007

Shirwan A. Mirza, MD, FACP, FACE,
Chairman: Department of Medicine
Auburn Memorial Hospital, Auburn, New York, 13021 USA
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Re: Celiac Disease: The great imitator

I would like to add the following highlights to the excellent review by Andrew D Hopper, et al.
Among atypical symptoms and presentations of celiac disease are anorexia, nausea, vomiting, severe constipation and failure to thrive. Epilepsy, and headache could be among atypical neuropsychiatric symptoms.
Ataxia may occur as a result of an immune-mediated process in the cerebellum.
Dental enamel defects are also more common among children and adults with celiac disease and suspected to be immunologically mediated.
About 25 percent of adults with celiac disease have arthritis Menstrual irregularities, recurrent miscarriage, and infertility are among other atypical presentations in women.
Celiac disease may be associated with mild chronic elevation in serum aminotransferase levels.
All patients with chronic refractory fatigue must be screened for celiac disease. Nutritional deficiencies are usually the underlying cause, especially vitamin D, B12 and iron deficiency. Lack of vitamin A may cause poor night visison.
HLA typing for DQ2 and DQ8 may have a diagnostic value in individuals with equivocal small bowel biopsy since celiac disease is unlikely if this genetic test is negative.
1. Nelsen DA Jr. Gluten-sensitive enteropathy (celiac disease): more common than you think. Am Fam Physician. 2002;66(12):2259-66.
2. Boscolo S, Sarich A, Lorenzon A, et al Gluten ataxia: passive transfer in a mouse model. Ann N Y Acad Sci. 2007;1107:319-28.
3. Hadithi M, von Blomberg BM, Crusius JB, et al Accuracy of serologic tests and HLA-DQ typing for diagnosing celiac disease. Ann Intern Med. 2007 Sep;147(5):294-302.
4. Gonz�lez-Abraldes J, S�nchez-Fueyo A, Bessa Xet al Persistent hypertransaminasemia as the presenting feature of celiac disease. Am J Gastroenterol. 1999;94(4):1095-7.
5. Ciacci C, Cirillo M, Auriemma G, Di Dato G, et al Celiac disease and pregnancy outcome. Am J Gastroenterol. 1996;91(4):718-22.
6. Smecuol E, Mauri�o E, Vazquez H, Pedreira S, et al Gynaecological and obstetric disorders in coeliac disease: frequent clinical onset during pregnancy or the puerperium. Eur J Gastroenterol Hepatol. 1996 Jan;8(1):63-89.
7. Djuric Z, Kamenov B, Kati Celiac disease manifested by polyneuropathy and swollen ankles. World J Gastroenterol. 2007;13(18):2636-8.
8. C�rdenas A, Kelly CP. Celiac sprue. Semin Gastrointest Dis. 2002 Oct;13(4):2
Competing interests: None declared

Coeliac disease: rheumatic presentations are common 16 September 2007

Alastair L Hepburn,
Consultant Rheumatologist
Worthing Hospital, Worthing BN11 2DH
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Re: Coeliac disease: rheumatic presentations are common

Hopper et al highlight the non-specific way in which coeliac disease can present in adults [1]. Presentations to rheumatology services are not uncommon with symptoms including fatigue, weakness, non-specific arthralgia, muscle cramps and myalgia. There is therefore a good argument for screening for this disease when patients present with what may appear initially to be fibromyalgia or chronic fatigue syndrome (CFS), using combined serological testing. Such screening for coeliac disease is included in the recently published NICE guidance on the management of CFS [2]. A true arthritis has also long been recognised [3, 4]. Presentation in the elderly is rare, but also described and deserves mentioning [4].
A gluten-free diet is the mainstay of treatment of the metabolic bone disease that may complicate coeliac disease. A mixture picture of osteomalacia and osteoporosis may be seen, and vitamin D replacement may have an additional role to improve both symptoms and to reduce the risk of fracture. A low serum vitamin D may be the only abnormality found on biochemical testing, and screening should be considered in patients with pre-menopausal and male osteoporosis. Presentation with a mixed deficiency anaemia is also possible, rather than iron deficiency alone, a low serum folate in particular being a fairly sensitive early indicator of the disease. Finally, coeliac disease may develop in patients with primary autoimmune rheumatic disease such as systemic lupus erythematosus and Sjogren's syndrome, and vice versa.
Occasionally non-specific musculoskeletal presentations may lead to the erroneous prescriptions of corticosteroids. This may lead to false- negatives on subsequent duodenal biopsy. However, corticosteroids may improve both gastrointestinal and musculoskeletal symptoms, and may be used to treat refractory disease. Other forms of immunosuppression, such as azathioprine and infliximab are also be used in refractory cases [5].
References:
1. Hopper AD, Hadjivassiliou M, Butt, S, Sanders DS. Adult coeliac disease. BMJ 2007; 335: 558-62.
2. NICE clinical guideline no. 53. Chronic fatigue syndrome / Myalgic encephalomyelitis (or encephalopathy): Diagnosis and management of CFS/ME in adults and children. National Institute for Health and Clinical Excellence. August 2007.
3. Bourne JT, Kumar P, Huskisson EC. Arthritis and coeliac disease. Ann Rheum Dis 1985; 44: 592-98.
4. Hepburn AL, Kaye SA. Oligoarthritis in an elderly woman with diarrhoea and weight loss. Postgrad Med J 2001; 77: 475-77.
5. Turner SM, Moorghen M, Probert CS. Refractory coeliac disease: remission with infliximab and immunomodulators. Eur J Gastroenterol Hepatol 2005; 75: 667-69.
Competing interests: None declared

British guidelines on necessity of bone densitometry in coeliac disease 17 September 2007

Robert J Mead,
SpR gastroenterology
Portsmouth Hospitals NHS Trust,
Moses Duku, Pradeep Bhandari, Suzie Green.
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Re: British guidelines on necessity of bone densitometry in coeliac disease

One of the great difficulties being a doctor is managing the volume of information you receive. I think whenever possible we should try and sing from the same songsheet, so it was a little disappointing that the latest British guidelines were not mentioned. The British Society of Gastroenterology produced guidelines on the management of osteoporosis in coeliac disease in June 2007. They recommend a different approach to the 2001 American guidelines but do recognise the lack of firm evidence for this.
They recommend DEXA scan testing in those with 2 or more of the following ;Persisting symptoms on gluten-free diet for 1 year or poor adherence to gluten-free diet; Weight loss >10%; BMI < 20; Age >70. They state that these gudelines should be interpreted in light of other osteoporotic fracture risk factors. They do not reccomend routine testing with DEXA scan either at diagnosis or at follow up. They also provide helpful general advice and treatment guidelines.
I think British doctors should follow British guidelines unless there is compelling new evidence. www.bsg.org.uk. Clinical Practice, Guidelines.
Competing interests: None declared

Unexplained Anemia. 19 September 2007

Mohammad Shaikhani,
Consultant physician
Sulaimanyah-Iraqi Kurdistan 0532
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Re: Unexplained Anemia.

Unexplained anemia is a frequent cause of consultantion for gastroenterologists for doing upper GIT endoscopy with duodenal biopsies for considering diagnosis of Celiac disease. This point was not stressed upon enough in the review, to my opinion & only mentioned in one of the tables. I think that this issue needs more emphasis.
Competing interests: None declared

Association between anorexia nervosa and coeliac disease 21 September 2007

Luca Mascitelli,
Chief of Sanitary Service
8 Via S. Agostino, Udine 33100 Italy,
Francesca Pezzetta
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Re: Association between anorexia nervosa and coeliac disease

In their excellent review (1), Hopper and colleagues, among the disorders associated with coeliac disease, do not mention anorexia nervosa. Although data in literature are based only on case reports (2-4), the association between anorexia nervosa and coeliac disease should deserve attention: the dietary restriction associated with a gluten-free diet could initiate an eating disorder; furthermore, in patients with a defined diagnosis of anorexia nervosa, the onset of coeliac disease could increase the medical complications associated with anorexia. Thus, coeliac disease should be considered in the differential diagnosis of eating disorders (5) but physicians should also be extremely vigilant for the diagnosis of anorexia nervosa in patients with coeliac disease.
Luca Mascitelli, MD Comando Brigata alpina �Julia� Udine, Italy 33100
Francesca Pezzetta, MD Ospedale di San Vito al Tagliamento San Vito al Tagliamento, Italy 33078
REFERENCES 1. Hopper AD, Hadjivassiliou M, Butt, S, Sanders DS. Adult coeliac disease. BMJ 2007;335:558-62.
2. Ricca V, Mannucci E, Calabr� A, Bernardo MD, Cabras PL, Rotella CM. Anorexia nervosa and celiac disease: two case reports. Int J Eat Disord 2000;27:119-22.
3. Yucel B, Ozbey N, Demir K, Polat A, Yager J. Eating disorders and celiac disease: a case report. Int J Eat Disord 2006;39:530-2.
4. Leffler DA, Dennis M, Edwards George JB, Kelly CP. The interaction between eating disorders and celiac disease: an exploration of 10 cases. Eur J Gastroenterol Hepatol 2007;19:251-5.
5. Levine RL. Endocrine aspects of eating disorders in adolescents. Adolesc Med 2002;13:129-43.
Competing interests: None declared