Letters to the Editor

Table 1. Studies assessing diagnostic outcomes in self-reported gluten sensitivity N

Mean age


















Kabbani et al. (1)



Aziz et al. (2)


Coburn et al. (3) Kaukinen et al. (4)

Gluten challenge, dosage, and duration?

CD diagnostic criteria

Final diagnosis


Yes in all cases, dosage not specified, at least 6–8 weeks

Positive TTG/ DGP + villous atrophy

42.4% CDa, 52.5% NCGS, 3.8% NCE, 1.3% indeterminate



Yes in HLA-DQ positive, ≥3 g of gluten/day for 2 weeks

Positive TTG/EMA + LD to villous atrophy

7% CD, 93% NCGS




Yes in 56 cases, half declined gluten challenge, dosage and duration not specified

Positive TTG/ EMA + villous atrophy

2% CD, 20% LD, 78% NCGS




Yes in all cases, dosage not specified, majority at least 1 month

Villous atrophy

9% CD, 8% LD, 20% cereal allergy, 63% NCGS

CD, celiac disease; DGP, deaminated gliadin peptide antibodies; EMA, endomysial antibody; LD, lymphocytic duodenosis; NCE, nonceliac enteropathy; NCGS, nonceliac gluten sensitivity; TTG, tissue tranglutaminase antibody. a Two cases were seronegative CD.

individuals specifically presenting with selfreported gluten sensitivity, a finding of LD in association with a positive celiac serology (tissue transglutaminase and/or endomysial antibodies) and correct HLA-DQ typing would be supportive of CD. However, recent reports have now suggested that LD may also occur in NCGS—that is, in cases of self-reported gluten sensitivity but with negative serology (7). The clinical evaluation performed by Kabbani et al. did not identify any such patient, and hence this form of presentation was not considered as part of the subsequent diagnostic model proposed. Nevertheless, previous studies (including those listed in Table 1) have noted LD in the context of negative serology (8). Identification of such individuals is important because, although they may fulfil the current criteria for NCGS, other causations need to be excluded, including CD, given that a proportion will be HLADQ positive and demonstrate endomysial antibodies on the duodenal culture medium despite the negative serology (8–11). We feel that the algorithm proposed should incorporate such diagnostically challenging patients, considering them as an “indeterminate” group. In summary, the data shown suggest that self-reported gluten sensitivity is an international concept. We would like to take this opportunity to congratulate Kabbani et al. for their significant efforts in exploring this complex clinical entity and © 2014 by the American College of Gastroenterology

providing a platform from which a consensus can now be reached. CONFLICT OF INTEREST The authors declare no conflict of interest. REFERENCES 1. Kabbani TA, Vanga RR, Leffler DA et al. Celiac disease or non-celiac gluten sensitivity? an approach to clinical differential diagnosis. Am J Gastroenterol 2014;109:741–6. 2. Aziz I, Lewis NR, Hadjivassiliou M et al. A UK study assessing the population prevalence of self-reported gluten sensitivity and referral characteristics to secondary care. Eur J Gastroenterol Hepatol 2014;26:33–9. 3. Coburn JA, Vande Voort JL, Lahr BD et al. Human leukocyte antigen genetics and clinical features of self-treated patients on a gluten-free diet. J Clin Gastroenterol 2013;47:828–33. 4. Kaukinen K, Turjanmaa K, Mäki M et al. Intolerance to cereals is not specific for coeliac disease. Scand J Gastroenterol 2000;35:942–6. 5. Leffler D, Schuppan D, Pallav K et al. Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. Gut 2013;62:996–1004. 6. Aziz I, Evans KE, Hopper AD et al. A prospective study into the aetiology of lymphocytic duodenosis. Aliment Pharmacol Ther 2010;32:1392–7. 7. Sapone A, Bai JC, Ciacci C et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med 2012;10:13. 8. Carroccio A, Mansueto P, Iacono G et al. Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. Am J Gastroenterol 2012;107:1898–906; quiz 1907. 9. Molina-Infante J, Santolaria S, Fernandez-Bañares F et al. Lymphocytic enteropathy, HLA-DQ2/ DQ8 genotype and wheat-dependent symptoms:

non-celiac wheat sensitivity or Marsh I celiac disease? Am J Gastroenterol 2013;108:451. 10. Carroccio A, Mansueto P. Response to MolinaInfante et al. Am J Gastroenterol 2013;108: 451–2. 11. Carroccio A, Iacono G, Di Prima L et al. Antiendomysium antibodies assay in the culture medium of intestinal mucosa: an accurate method for celiac disease diagnosis. Eur J Gastroenterol Hepatol 2011;23:1018–23. 1

Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK; 2Department of Neurology, Royal Hallamshire Hospital, Sheffield, UK. Correspondence: Imran Aziz, MRCP, Department of Gastroenterology, Royal Hallamshire Hospital, Room P39, Sheffield S10 2JF, UK. E-mail: [email protected]

Response to Aziz et al. Toufic A. Kabbani, MD, MPH1, R.R. Vanga1,2, D.A. Leffler1,2, J. Villafuerte1,2, K. Pallav1,2, J. Hansen1,2, R. Mukherjee1,2, M. Dennis1,2 and Ciaran Kelly, MD2 doi:10.1038/ajg.2014.267

To the Editor: While there has been heightened national and international awareness of celiac disease (CD) and, more recently, non-celiac gluten sensitivity (NCGS), there remain numerous large gaps in our understanding of the pathophysiology and natural history of NCGS (1). Moreover, gluten challenge, albeit necessary to establish a true CD diagnosis in some subjects with clinical The American Journal of GASTROENTEROLOGY



Letters to the Editor

response to gluten elimination, constitutes a major source of discomfort and concern for patients and their families (2). We reviewed the thoughtful commentary by Aziz et al. (3) in response to our paper entitled: “Celiac Disease or Non-Celiac Gluten Sensitivity? An Approach to Clinical Differential Diagnosis” (4). We cannot but agree that a consensus should be reached in our approach to diagnosis and care for the growing number of patients with symptoms related to gluten ingestion. Equally important is establishing new biomarkers and noninvasive diagnostic modalities so as to eliminate the need for the “obsolete and cumbersome” gluten challenge test. In this context, our group reported that a shorter challenge with a low gluten diet (3 g/day) is sufficient to induce changes consistent with CD in most individuals (5). To date, several important questions on CD and NCGS remain unanswered. While it was proposed that NCGS and CD could be on the same continuum (6), this is highly questionable; there are many HLA-DQ2/8 negative patients with NCGS suggesting that these two entities are pathophysiologically distinct. Although an increase in intraepithelial lymphocytes can be an early finding in CD, it is nonspecific and also occurs in a wide range of other conditions. Hence, in the absence of other diagnostic markers, an isolated increase in intraepithelial lymphocytes is not sufficient to diagnose CD (absent positive test results for specific CD serologies). To further complicate an already murky diagnostic arena, there is growing evidence that gluten exposure alone is not responsible for symptoms in “gluten sensitive” subjects on a low FODMAP diet (7). This indicates that the symptoms of at least a subgroup of NCGS subjects are not solely related to gluten. If this is truly the case, it is not surprising that these subjects test negative for specific celiac serologies. In summary, “between celiac disease and irritable bowel syndrome: the no man’s land of gluten sensitivity” (8) continues to pose perplexing diagnostic questions. Nonetheless, and despite the lack of a full understanding of the pathophysiology of NCGS, it remains crucial to frame a simplified algorithm that guides in clinical differential diagnosis; one thing that we attempted in our article. The American Journal of GASTROENTEROLOGY

CONFLICT OF INTEREST The authors declare no conflict of interest. REFERENCES 1. Biesiekierski JR, Newnham ED, Irving PM et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a doubleblind randomized placebo-controlled trial. Am J Gastroenterol 2011;106:508–14; quiz 515. 2. Brottveit M, Beitnes AC, Tollefsen S et al. Mucosal cytokine response after short-term gluten challenge in celiac disease and nonceliac gluten sensitivity. Am J Gastroenterol 2013;108:842–50. 3. Aziz I, Hadjivassiliou M, Sanders DS. Selfreported gluten sensitivity: an international concept in need of consensus? Am J Gastroenterol 2014;109:1498–9 (this issue). 4. Kabbani TA, Vanga RR, Leffler DA et al. Celiac disease or non-celiac gluten sensitivity? An approach to clinical differential diagnosis. Am J Gastroenterol 2014;109:741–6. 5. Leffler D, Schuppan D, Pallav K et al. Kinetics of the histological, serological and symptomatic responses to gluten challenge in adults with coeliac disease. Gut 2013;62: 996–1004. 6. Ball AJ, Hadjivassiliou M, Sanders DS. Is gluten sensitivity a ‘‘No Man’s Land’’ or a ‘‘Fertile Crescent’’ for research? Am J Gastroenterol 2010;105:222–3; author reply 223-4. 7. Biesiekierski JR, Peters SL, Newnham ED et al. No effects of gluten in patients with selfreported non-celiac gluten sensitivity after dietaryreduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology 2013;145:320–8. 8. Verdu PF, Armstrong D, Murray JA. Between celiac disease and irritable bowel syndrome: the ‘‘no man’s land’’ of gluten sensitivity. Am J Gastroenterol 2009;104:1587–94. 1

Beth Israel Deaconess Medical Center, Division of Gastroenterology, Boston, Massachusetts, USA; Beth Israel Deaconess Medical Center, Division of Gastroenterology, Harvard Medical School, Boston, Massachusetts, USA. Correspondence: Toufic A. Kabbani, MD, MPH, Beth Israel Deaconess Medical Center, Division of Gastroenterology, 330 Brookline Avenue, Dana 603, Boston, Massachusetts 02215, USA. E-mail: [email protected]


NAFLD Is Underrecognized in The Primary Care Setting: UK Experience Matthew J. Armstrong, PhD, MRCP1, Diarmaid D. Houlihan, PhD, MRCP2 and Philip N. Newsome, PhD, FRCP1 doi:10.1038/ajg.2014.207

To the Editor: We read with interest the article by Blais et al., (1) which raises important concerns regarding the lack of recognition of significant nonalcoholic fatty liver disease (NAFLD) in primary care in the United States. In support, our large prospective primary care study (n = 1,118) from the United Kingdom highlighted that NAFLD (clinical and ultrasound defined) accounts for over 25% of incidental abnormal liver function tests in primary care consultations, in which the clinical suspicion of liver disease was absent (2). The majority of patients with NAFLD (57.2%) had advanced fibrosis excluded by means of a low NAFLD Fibrosis Score (NFS < − 1.455). However, in keeping with the findings of Blais et al. (1) a concerning proportion (7.6%) had undetected advanced fibrosis (NFS > 0.675) in our study (2). Even though the natural history of NAFLD remains largely unknown in primary care, our findings in conjunction with those of Blais and colleagues highlight that a significant proportion of patients with NAFLD and advanced fibrosis will fail to benefit from recommended surveillance of life-threatening complications (i.e., hepatocellular carcinoma, variceal hemorrhage). Despite the fact that the most promising pharmaceutical options for NAFLD are still in phase II/III stages of clinical trials, there is good evidence that intense lifestyle modifications (i.e., weight loss) result in histological improvements in NAFLD (3,4). Therefore, without a focused approach to improve clinical awareness of NAFLD in primary care, patients with this predominantly ‘‘silent’’ disease will remain disadvantaged and the disease burden will continue to grow exponentially. In the absence of validated tools, we would strongly advocate the use of the simple, noninvasive NFS in primary care to identify those patients in greatest need of intense lifestyle modifications, cardiovascular risk management, surveillance, and secondary care input. CONFLICT OF INTEREST The authors declare no conflict of interest. REFERENCES 1. Blais P, Husain N, Kramer JR et al. Nonalcoholic fatty liver disease is underrecognized in

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Response to Aziz et al.

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