paper1 (11)

8/11/2019 paper1 (11)

1/10204 | APRIL 2010 | VOLUME 7 www.nature.com/nrgastro

Department ofGastroenterology andHepatology (G. J. Tack,W. H. M. Verbeek,C. J. J. Mulder),Department ofPathology(M. W. J. Schreurs),VU University MedicalCenter, P. O. Box 7057,1007 MB Amsterdam,The Netherlands.

Correspondence to:G. J. [email protected]

The spectrum of celiac disease:

epidemiology, clinical aspects and treatmentGreetje J. Tack, Wieke H. M. Verbeek, Marco W. J. Schreurs and Chris J. J. Mulder

Abstract | Celiac disease is a gluten-sensitive enteropathy that affects people of all ages worldwide. This

disease has emerged as a major health-care problem, as advances in diagnostic and screening methods have

revealed its global prevalence. Environmental factors such as gluten introduction at childhood, infectious

agents and socioeconomic features, as well as the presence of HLA-DQ2 and/or HLA-DQ8 haplotypes

or genetic variations in several non-HLA genes contribute to the development of celiac disease. Growing

insight into the variable clinical and histopathological presentation features of this disease has opened

new perspectives for future research. A strict life-long gluten-free diet is the only safe and efficient available

treatment, yet it results in a social burden. Alternative treatment modalities focus on modification of dietary

components, enzymatic degradation of gluten, inhibition of intestinal permeability and modulation of theimmune response. A small group of patients with celiac disease (25%), however, fail to improve clinically and

histologically upon elimination of dietary gluten. This complication is referred to as refractory celiac disease,

and imposes a serious risk of developing a virtually lethal enteropathy-associated T-cell lymphoma.

Tack, G. J. et al. Nat. Rev. Gastroenterol. Hepatol.7, 204213 (2010); published online 9 March 2010; doi:10.1038/nrgastro.2010.23

Introduction

Celiac disease is the most common food intolerancein the Western population, and currently represents amajor health-care issue. Celiac disease has an ancienthistory, first described in the 1stand 2ndcentury AD.In 1887, Samuel Gee described typical symptoms ofceliac disease in children, including irritability, chronic

diarrhea and failure to thrive, and cure by means ofa diet was suggested for the first time.1Since then,insight into celiac disease has undergone a revolution-ary development regarding epidemiology, diagnosticsand treatment.

Celiac disease is a chronic, small-intestinal entero-pathy, which is triggered by gluten proteins from wheat,barley and rye. Celiac disease is characterized by anautoimmune response in genetically susceptible indivi-duals resulting in small-intestinal mucosal injury. As aconsequence, malabsorption develops, which resultsin malnutrition-related problems including anemia,vitamin deficiencies, osteoporosis , and neurolog ical

disorders. Withdrawal of dietary gluten usually leads toprompt healing of the damaged small-intestinal mucosaand improvement of nutrient absorption. A gluten-freediet is sufficient to treat the overwhelming majority ofpatients with celiac disease and clinical improvement isusually evident within a few weeks.2

A small percentage (25%) of patients with adult-onsetceliac disease, especially those diagnosed above the ageof 50, does not respond to a gluten-free diet and is seenas suffering from refractory celiac disease (RCD). Theoccurrence of an enteropathy-associated T-cell lym-phoma (EATL) is the major complication associated

with RCD and is the main cause of death in this patientgroup.3,4Early identification of patients with RCDenables early intervention, which results in reduction inmorbidity and mortality.4,5

This Review gives an overview of the latest trends in epi-demiology, clinical course, diagnostics, complications andtreatment with respect to the spectrum of celiac disease.

Epidemiology

Global population trends

Until the 1970s the estimated global prevalence of celiacdisease in the general population was 0.03%.6The cur-rently estimated prevalence is 1%, with a statistical range

of probability of 0.51.26% in the general population inEurope and the USA.7Even taking into account thatthe actual occurrence rate of celiac disease has beenunderestimated for many decades, the prevalence of thisdisease is increasing. Advances in diagnostic methodsand improvement in screening have played a part in theincrease observed, but environmental factors have alsobeen important.

Trends in diagnosis and screening

The introduction of gastrointestinal endoscopic tech-niqueswhich provided the opportunity to take routinebiopsy samplesin the 1970s opened new horizons in

Competing interests

G. J. Tack declares an association with the following company:AstraZeneca. C. J. J. Mulder declares an association with thefollowing companies: AstraZeneca, DSM Food Specialties,Fujinon, Janssen-Cilag, Nycomed. See the article online for fulldetails of the relationships. The other authors declare nocompeting interests.

REVIEWS

20 Macmillan Publishers Limited. All rights reserved10
mailto:[email protected]://www.nature.com/doifinder/10.1038/nrgastro.2010.23http://www.nature.com/doifinder/10.1038/nrgastro.2010.23mailto:[email protected]

8/11/2019 paper1 (11)

2/10NATURE REVIEWS|GASTROENTEROLOGY & HEPATOLOGY VOLUME 7 | APRIL 2010 | 205

celiac disease case-f inding and diagnosis. In addition,identification of two human leukocyte antigen (HLA)molecules typically associated with celiac disease,HLA-DQ2 and HLA-DQ8, in the late 1980s and early1990s, respectively,8and development of highly sensi-tive and specific serologic tests have also been important.Furthermore, the implementation, since the late 1980s,of screening programs for detecting celiac disease hascontributed to a more realistic estimate of the actualdisease prevalence.9The recognition that atypical, minoror extraintestinal complaints can be associated withceliac disease in patients of all ages and the detection ofa range of histological abnormalities in the small intes-tine of patients with the disease have also contributed toimproved diagnosis.1012

Despite the advances in screening for celiac disease,it remains underdiagnosed.13In the general popula-tion, the ratio between patients with celiac disease whoreceived an accurate diagnosis and those who were neverdiagnosed as having the disease was reported to rangefrom 1:5.513up to 1:10.14Since the 1980s, a trend towards

earlier diagnosis of celiac disease has been observed.15Unawareness of celiac disease by physicians probably stillunderlies misdiagnosis and diagnostic delay.

Environmental risk factors

A Finish population-based study has shown that thealmost doubled prevalence of celiac disease observed from1980 (1.03%) to 2001 (1.99%) could not be ascribed onlyto screening and improved diagnostics, but was rathermost probably attributable to environmental changes.6,16

Infant feeding

The role of infant feeding on the development of celiac

disease has been intensely debated since the late 1980s,which has resulted in a recommendation by the EuropeanSociety for Paediatric Gastroenterology, Hepatology andNutrition (ESPGHAN) committee.17This committeecurrently recommends that small amounts of gluten aregradually introduced between 4 and 7 months of ageduring breastfeeding.17This recommendation is stronglysupported by a meta-analysis18and, moreover, by lessonslearned from the Swedish epidemic of celiac disease(19841996), which arose as a consequence of changesin infant feeding.19In this birth cohort, gluten was mainlyintroduced abruptly after discontinuing breastfeeding at6 months of age. At the same time, the gluten content of

commercial infant food was increased. The prevalenceof celiac disease was almost threefold higher in this birthcohort compared with that in infants born after the epi-demic, in whom gluten was introduced gradually whilecontinuing breastfeeding.19Although dietary gluten expo-sure in children under the age of two seems more impor-tant with respect to celiac disease risk when comparedwith exposure in older children,19whether breastfeedingonly delays clinical onset or whether it leads to permanentprotection against celiac disease remains to be elucidated.Interestingly, one study has suggested that breastfeedingduring gluten introduction, which slightly delays onsetof celiac disease, also influences clinical appearance as

Key points

Celiac disease is a gluten-sensitive enteropathy that has emerged as a major

health-care problem, as its global prevalence is increasing

Advances in diagnostic and screening methods have contributed to the

apparent increase in disease prevalence, but evidence also suggeststhe existence of a real increase caused by environmental changes

Diverse environmental, genetic and socioeconomic factors contribute to thedevelopment of celiac disease

Growing insight into the clinical presentation of celiac disease has resulted innovel diagnostic, prognostic and therapeutic dilemmas

Although alternative treatment modalities that reduce the need of dietingare being developed, the only safe and effective therapy available so far is a

life-long gluten-free diet

25% of patients with celiac disease develop refractor y celiac disease,a serious complication that is associated with a 50% risk of developing

lymphoma, which has a poor prognosis

well. Among children who develop celiac disease duringgluten introduction, those who were breastfed at the sametime can present the typical (49%) or atypical (51%) form

of disease, whereas the ones in which gluten introductionoccurred after breastfeeding was stopped more frequentlydevelop typical gastrointestinal symptoms (90%).20

Infections

Infections after birth have been proposed to contributeto the development of celiac disease. Whereas the role ofinfection with adenovirus type 12 in this process remainscontroversial, the association of HCV infection and celiacdisease is well documented.21A prospective study showedthat frequent rotavirus infections, the most common causeof childhood gastroenteritis, represent an independent riskfactor for celiac disease in genetically susceptible indivi-

duals.22Rotavirus infection changes the permeability ofand the cytokine balance in the intestinal mucosa, poten-tially enhancing penetration of gluten peptides.22If thisis the case, worldwide implementation of a rotavirusvaccine might diminish the occurrence of celiac disease.The influence of infections with other common intestinalmicroorganisms, including Campylobacter jejuni, Giardialambliaand enterovirus has not yet been clarified.23

Socioeconomic features

An epidemiological survey where comparisons were madebetween schoolchildren living in a prosperous area ofFinland and children living in an adjacent poor region

of Russia, whom in part shared genetic susceptibility andgluten intake, has suggested that worse socioeconomicconditions might protect against celiac disease develop-ment.24Variation in gut flora, infections and differencesin diet, which are factors involved in the maturation ofimmunoregulatory functions, may in turn precipitateceliac disease development.24

Genetic risk factors

HLA genes

Celiac disease is a multigenic disorder, in which the mostdominant genetic risk factors are the genotypes encod-ing the HLA class II molecules HLA-DQ2 (encoded by

REVIEWS


8/11/2019 paper1 (11)


HLA-DQA1*0501and HLA-DQB1*02) and HLA-DQ8(encoded by HLA-DQA1*0301and HLA-DQB1*0302).About 90% of individuals with celiac disease carry theDQ2 heterodimer encoded either in cisor in trans, andpractically all of the remaining patients express DQ8.8Deamidated gliadin peptides have a high binding affin-ity to HLA-DQ2 and HLA-DQ8 molecules, but not

to other HLA class II molecules, which explains theimmunogenicity of gluten in carriers of HLA-DQ2and HLA-DQ8. A correlation has been found betweenhomozygosity for the genes encoding the HLA-DQ2molecule and the development of serious complicationsof celiac disease, in particular RCD and EATL, whichimplies a genedose effect.25These HLA-encoding genesare associated with approximately 40% of the heritablerisk of developing celiac disease.26

Non-HLA genes

Currently, several susceptibility loci not related to HLAhave been identified by genome-wide association studies,

each of which is estimated to be associated with only asmall risk of developing celiac disease. Most of these locicontain immune-related genes, in particular genes impli-cated in the control of the adaptive immune response.The proteins encoded by these genes include an integrin(encoded by ITGA4at 2q31),27chemokines, cytokinesand their receptors (IL2and IL21at 4q27, IL18RAPat2q112q12, IL12Aat 3q253q26, the CCR1and CCR3cluster locus at 3p21), and proteins involved in severalsignaling pathways (RGS1at 1q31, SH2B3at 12q24,ATXN2at 12q24, TNFAIP3at 6q23.3, REL at 2p16.1), inregulating B-cell (RGS1) and T-cell activation (TAGAPat 6q25), and in maintaining cell adhesion and motility(LPPat 3q28).28,29However, association between the riskof celiac disease development and CCR3and IL18RAPcould not be confirmed in other studies.27,30The 4q27region, which harbors the IL2and IL21genes, showed thestrongest association.27,29The latter association, however,accounted for less than 1% of the familial risk of celiacdisease and genetic variation in all currently knownnon-HLA genes together accounts for less than 10%.27,29

This indicates that many contributing polymorphisms innon-HLA genes still have to be discovered. An associa-tion betweenMYO9Bpolymorphisms and an increasedrisk for RCD and EATL has been found, however foruncomplicated celiac disease this association remainscontroversial.31Further research is needed to determinethe functions of the proteins that these genes encode andtheir involvement in the pathogenesis of celiac disease.

Population, gender and age distribution

Variety in genetic factors including the frequency ofnon-HLA alleles, and environmental factors includingdietary habits underlie the variations in the frequency

of celiac disease observed in different world regions(Table 1). The HLA-DQ2 heterodimer is frequentlyfound in white populations in Western Europe (2030%),Northern and Western Africa, the Middle East andcentral Asia, whereas HLA-DQ8 is more prevalent inLatin America and Northern Europe.32Gluten con-sumption is widespread in Northern Africa, SouthAmerica and the northern wheat-eating parts of India.The Saharawi population of Arab-Berber origin living inAlgeria has the highest prevalence of celiac disease (5.6%)among all world populations.33High levels of consan-guinity, high frequencies of HLA-DQ2 and gluten beingused as staple food in this population may potentially

explain this finding.33By contrast, celiac disease seems tobe rare in individuals of Japanese and Chinese ancestry,for whom the frequency of HLA-DQ2 is negligible.32Theoccurrence of celiac disease may vary within individualcountries, for instance in different parts of India. 34,35This variation is probably attributable to differencesin dietary habits and to associations between specificgenetic clusters and particular regions. Middle Easterncountries, including Iran, Turkey, Israel and Syria, seemto have similar frequency rates of celiac disease to thoseof Western countries.36

As expected, in high-risk populations the prevalenceof celiac disease is much higher than that in the general

Table 1 | Worldwide prevalence of celiac disease in children and adults

Country Adults Children

Europe

Czech Republic 0.45%84 NA

Finland 0.552.0%6,14 1.0%42

Germany 0.19%85 0.2%85

Great Britain 1.2%86

1.0%87

Italy 0.18%88 0.540.85%89,90

Northern Ireland 0.82%91 NA

Russia 0.20%24 NA

Spain 0.26%92 NA

Sweden 0.460.53%93 1.3%94

The Netherlands 0.35%95 0.5%96

North and South America

Argentina 0.6%97 NA

Brazil 0.15%98 NA

Mexico 2.6%99 NA

USA 0.40.95%7,37

0.90.31%7,40

Asia

India NA 1.0%34,100

Iran 0.6%101 0.6%102

Israel 0.6%103 0.17%103

Kuwait NA 0.02%104

Syria 1.6%32. NA

Turkey 1.3%105 0.9%106

Africa

Algeria NA 5.6%33

Tunisia 0.28%107 0.64%108

OceaniaAustralia 0.4%109 NA

New Zealand 1.2%110 NA

Abbreviation: NA, not available.

REVIEWS


8/11/2019 paper1 (11)


population. A multicenter study conducted in the USArevealed that the prevalence of serotypes associatedwith risk of disease was 1:56 in individuals with clini-cal features of celiac disease or celiac-disease-associatedextraintestinal disorders.37Furthermore, the prevalenceof risk-associated serotypes in first-degree and second-degree relatives of these patients was 1:22 and 1:39,respectively. In adults and children with symptoms thatraise suspicion of celiac disease, prevalence rates of 1:68and 1:25, respectively, were observed.

As with many other autoimmune diseases, celiacdisease is more common in women,38with a female tomale ratio of between 2:1 and 3:1. Some genetic loci aregender-influenced and immunoregulation is subject tohormones, which might explain these differences. Bycontrast, patients over the age of 60 who are diagnosedas having celiac disease are more frequently male.39

Celiac disease can be diagnosed at any age, with a peakat early childhood and at the fourth and fifth decade oflife for women and men, respectively. Currently, thereported global prevalence of celiac disease in children

ranges from 0.31% to 0.9%.7,40The prevalence of celiacdisease in adults is approximately 12% in Europe6and0.40.95% in the USA.7Whether diagnosing celiacdisease at advanced age is the result of diagnostic delay orof a true late onset of the disease is still debated. Whereasseveral studies reported a diagnostic delay in the elderlypopulation,41other reports suggest that celiac diseasemay indeed develop later in life.12,16

Clinical presentation

Celiac disease has long been considered a pediatric syn-drome, in which classical intestinal symptoms, includ-ing diarrhea, steatorrhea and weight loss predominate.

However, the disease has been increasingly diagnosedin older children and adults and has emerged to encom-pass a broad spectrum of clinical manifestations (Box 1),which are associated with a large variety of changes in themucosa of the small intestine.10,11About 50% of patientswith celiac disease present with atypical symptoms, suchas anemia, osteoporosis, dermatitis herpetiformis, neuro-logical problems and dental enamel hypoplasia.15,42,43The variable clinical picture of celiac disease is thoughtto have both genetic and immunological bases. Age ofonset, extent of mucosal injury and dietary habits, butalso gender,44seem to affect the clinical manifestationof the disease.

The spectrum of celiac disease currently encompassesfour different types of which clinicians should be aware.45The classical form, which is mainly diagnosed between6 and 18 months of age, is characterized by villousatrophy and typical symptoms of intestinal malabsorp-tion. The atypical form is characterized by architecturalabnormalities of the small intestinal mucosa and minorintestinal symptoms. Patients with this form presentpredominantly with various extraintestinal signs andsymptoms, such as osteoporosis, peripheral neuropathy,anemia and infertility. The latent form is defined by pres-ence of HLA-DQ2 and/or HLA-DQ8 molecules, normalarchitecture of the intestinal mucosa and possibly positive

Box 1| Clinical presentation of celiac disease

Typical signs and symptoms

Abdominal distension

Abdominal pain

Anorexia

Bulky, sticky and pale stools

Diarrhea

Flatulence

Failure to thrive

Muscle wasting

Steatorrhea

Vomiting

Weight loss

Atypical signs and symptoms

Alopecia areata

Anemia (iron deficiency)

Aphthous stomatitis

Arthritis

Behavioral changes

Cerebellar ataxia

Chronic fatigue

Constipation

Dental enamel hypoplasia

Dermatitis herpetiformis

Epilepsy

Esophageal reflux

Hepatic steatosis

Infertility, recurrent abortions

Isolated hypertransaminasemia

Late-onset puberty

Myelopathy

Obesity

Osteoporosis/osteopenia

Peripheral neuropathy

Recurrent abdominal pain

Short stature

Associated diseases

Addison disease

Atrophic gastritis

Autoimmune hepatitis

Autoimmune pituitaritis

Autoimmune thyroiditis

Behet disease

Dermatomyositis

Inflammatory arthritis

Myasthenia gravis

Primary biliary cirrhosis

Primary sclerosing cholangitis

Psoriasis

Sjgren disease

Type 1 diabetes mellitus

Vitiligo

REVIEWS


8/11/2019 paper1 (11)


serology. Extraintestinal signs and symptoms may or maynot occur. In this form of disease, the gluten-dependentchanges appear later in life. The silent form is markedby small intestinal mucosal abnormalities and in mostcases by positive celiac-disease-associated serology, butis apparently asymptomatic.

Patients with the nonclassical forms of the diseaseare usually detected by screening of high-risk popula-tions or during upper-endoscopic analysis for otherreasons. After starting a gluten-free diet, the majorityof patients, irrespective of the clinical presentation, willnotice improvement of their physical and psychologi-cal condition.46This improvement indicates that these

asymptomatic, apparently healthy individuals are indeedaffected by minor, unrecognized illness features such aslack of appetite, behavioral abnormalities and fatigue,which are most likely to be consequences of the pres-ence of the disease for years.

The prevalence of several autoimmune diseases,predominantly organ-specific diseases, is higher inpatients with celiac disease than in the general popula-tion (Box 1).47First-degree relatives of and patientswith Down, Turner or Williams syndromes are also atincreased risk for the development of celiac disease.48

Diagnosis

Given the broad clinical spectrum of celiac disease,accurate histological and serological testing is essentialfor correct diagnosis. The diagnosis algorithm of celiacdisease currently follows the revised ESPGHAN cri-teria, published in 1990.49Briefly, a positive diagnosisis made when the following features are both present:typical small-intestinal histopathological abnormali-ties defined as hyperplastic villous atrophy, and clini-

cal remission on a strict gluten-free diet with relief ofsymptoms within weeks. In asymptomatic individuals asecond biopsy is required to verify mucosal recovery afterwithdrawal of dietary gluten. The presence of circulatingceliac-disease-associated antibodies at time of diagnosisand their normalization after a gluten-free diet supporta diagnosis of celiac disease. As a consequence of theincreased appreciation of the variable clinical and histo-logical manifestations of the disease and improvementof serological and genetic tests, further revision of theESPGHAN criteria that takes into account the results ofmulticenter studies has been repeatedly advocated.10,50

Appropriate diagnosis of celiac disease is extremely

important to avoid lifelong unnecessary commitmentto a gluten-free diet in patients with other gastro-intestinal diseases and to enable rapid treatment ofpatients with celiac disease, which decreases the riskof complications.

Histopathological analysis

Histopathological analysis of small intestinal biopsysamples of individuals with celiac disease is character-ized by typical architectural abnormalities. These areclassified according to the modified Marsh classifica-tion:51normal mucosa (Marsh 0), intraepithelial lympho-cytosis (Marsh I), intraepithelial lymphocytosis and

crypthyperplasia (Marsh II), and intraepithelial lympho-cytosis, crypthyperplasia and villous atrophy (Marsh III).Mucosal villous atrophy has long been considered thehallmark of celiac disease and remains the gold stan-dard in celiac disease diagnosis. False-positive and false-negative diagnosis, however, may occur as a consequenceof interobserver variability, patchy mucosal damage,low-grade histopathological abnormalities and technicallimitations.52For example, patients with low-grade histo-pathological abnormalities (Marsh I or Marsh II) canpresent with gluten-dependent symptoms or disordersbefore overt villous atrophy occurs. Furthermore, severalpatients with isolated intraepithelial lymphocytosis

Celiac disease l ikely Celiac disease not excluded Celiac disease unlikely

Gluten-free diet Revison histopathologyRepeat biopsy periodically

Gluten withdrawaland/or challenge

Other diagnostical tests

Villous atrophy Marsh I/II Normal

Positive Negative

Serology IgA TGA and EMAIf IgA deficiency IgG TGA and EMA

Biopsy

Serology TGA and EMA (if not performed yet)

Negative

Celiac disease?

Moderate or low clinical suspicionStrong clinical suspicion

Figure 1| Algorithm for diagnosis of uncomplicated celiac disease. Abbreviations:EMA, endomysial antibodies; TGA, tissue transglutaminase antibodies.

Table 2 | Treatment of uncomplicated celiac disease

Therapeutic aims and approaches Therapies

Decrease gluten exposure

Manipulation or selection of dietarycomponents

Cereal modification111,112

Polymeric gliadin binders and neutralizers113

Enzymatic degradation of gluten Aspergillus niger-derived prolyl endopeptidase114

ALV003 enzyme cocktail115,116

Probiotics (VSL#3)117

Inhibit intestinal permeability

Zonulin inhibition Larazotide acetate118

Modulate the immune response

Decrease adaptive immune activity Blockers of tissue transglutaminase

antibodies119

Blockers of antigen presentation by HLA-DQ2

and HLA-DQ8120

Gluten peptide vaccine121

Infection with the hookworm Necator

americanus122

Reduce inflammation Interleukin 10123

REVIEWS


8/11/2019 paper1 (11)


(Marsh I), who are not clinically suspected of havingceliac disease, develop celiac disease during follow-up.50Although the mucosal changes in celiac disease arethought to develop gradually, whether minor mucosallesions in asymptomatic patients indicate celiac diseasein an early stage is not yet clear.53In case of strong clini-cal suspicion of celiac disease, duodenal biopsy mustbe performed regardless of serological analysis;54incases of low suspicion of disease or screening, duo-denal biopsy only needs to be performed in seropositivepatients (Figure 1).

Serological and genetic analyses

At present the most sensitive and specific serologicaltests for diagnosis of celiac disease are assessments of thepresence of IgA autoantibodies against the endomysiumof connective tissue (EMA) and against tissue trans-glutaminase (TGA).51Tests for antibodies against deami-dated gliadin peptides (which are part of gluten) havealso become available and are promising diagnostictools.55At diagnosis stage, at least anti-TGA antibodies

should be measured and, if detected, the diagnosis ofceliac disease should be preferably verified with assess-ment of anti-EMA antibodies. Assessment of gliadinantibodies is a less specific and sensitive test than anti-TGA and anti-EMA testing, except in children youngerthan 2 years of age, in whom measurement of antibodiesto gliadin is a more sensitive test.56An important pitfallin serological testing for celiac disease is the increasedprevalence of IgA deficiency observed in patients withthe disease compared with that in healthy individuals.57In order to avoid false-negative serological results incases of IgA deficiency, simultaneous monitoring ofserum IgA levels is required. In case of IgA deficiency,

screening for IgG antibodies (either to TGA or to EMA)should be performed.58

Although HLA-DQ2 and/or HLA-DQ8 positivity isnot an absolute requirement for diagnosis, as 40% ofthe healthy Western population also carry genotypesfor these molecules,8celiac disease is highly unlikelyin case both of them are absent. As a consequence ofthis high negative predictive value for developing celiacdisease, HLA genotyping was proposed as a contribut-ing element to diagnosis, in particular in the absenceof villous atrophy.59Case-finding of patients with low-grade histopathological features of celiac disease needsto be extended so that clinical studies that investigate the

precise role of genotyping as a first-line examination inthe diagnostic work-up can be started.

Furthermore, as negative serological testing does notexclude the development of celiac disease later in life,HLA genotyping has also been suggested as a powerfulscreening tool.60Nevertheless, this screening strategydoes not seem cost-saving compared with first-line sero-logical screening, although it might prevent unnecessaryanti-TGA and anti-EMA diagnostic testing.61The DutchMedical Celiac Disease Society recommends serologictesting in genetically susceptible patients for at least IgAantibodies against TGA every 2 and 5 years in adults andchildren, respectively.62

Treatment

The only currently available treatment for celiac diseaseconsists in dietary exclusion of grains containing glutenand supportive nutritional care in case of iron, calcium andvitamin deficiencies.63A life-long gluten-free diet is a

well tolerated therapy that improves health and qualityof life in the vast majority of patients with celiac disease,even in those with minimal symptoms.64This treatmentis, however, difficult to sustain, owing to small levelsof gluten contamination in food products, high costsand restricted availability of gluten-free food alterna-tives, and cultural practices leading to a substantial socialburden.65Therefore, in the past decade researchers havebecome increasingly interested in therapeutic alternativesfor continuous or intermittent use in patients with celiacdisease. Implementation of these is extremely challenging,as their potential adverse effects will always be difficultto accept as an alternative to a safe gluten-free diet.

Polyclonal

TCRgene rearrangementHistopathology Flow cytometry

SerologyDietician

Assess compliance to GFD

Biopsy Instruction by dieticianFollow-up 1 year

Sufficient complianceto GFD

(TGA/EMA negative)

Insufficient complianceto GFD

(TGA/EMA positive)

Revision of initial histopathology and serologyHLA genotyping

Refractory celiac disease?(symptoms despite GFD >1 year)

Reconsider initial diagnosis of celiac disease

Other diagnosis

Celiac disease likely EMA/TGA positive before GFD HLA-DQ2/8 positiveVillous atrophy

Celiac disease unlikely EMA/TGA never positive before GFDHLA-DQ2/8 negative No villous atrophy

Clonal20%aberrant IEL

Villousatrophy

Marsh 0II

RCD type I likely

Investigate EATL and other causes of villous atrophy

RCD type II likelyRCD unlikely

Figure 2| Algorithm for diagnosis of complicated celiac disease. Abbreviations:EATL, enteropathy-associated T-cell lymphoma; EMA, endomysial antibody test;GFD, gluten-free diet; IEL, intra-epithelial lymphocyte; RCD, refractory celiacdisease; TCR, T-cell receptor, chain; TGA, tissue transglutaminase antibody test.

REVIEWS


8/11/2019 paper1 (11)


Newly developed treatment modalities for celiacdisease are aimed at reducing the need for a strict gluten-free diet and are based on currently available insights intothe pathogenesis of the disease (Table 2). These therapies

focus on alteration of dietary food products, decreaseof gluten exposure by rapid enzymatic degradation,inhibition of small intestinal permeability or modula-tion of the immune response.66Clinical trials for someof these therapies are still ongoing. For the time being,strict adherence to a gluten-free diet should be advisedfor all patients with celiac disease, as it remains the onlyeffective and safe therapy, which also seems to reduce therisk of complications.67,68

Complications

The long-term consequences of celiac disease are amatter of debate, particularly since the recognition

of its broad clinical spectrum. The influence of non-compliance to a gluten-free diet and the substantialnumber of patients being undiagnosed are of greatestconcern, as these factors could possibly contribute to therefractory form of celiac disease and to the developmentof malignancies.

Refractory celiac disease

Some patients with adult-onset celiac disease, especiallyamong those diagnosed above the age of 50, show a lackof response to a gluten-free diet. They are diagnosed ashaving RCD when clinical and histological symptomspersist or recur after a former good response to a strict

gluten-free diet and despite strict adherence to the dietfor more than 12 months, unless earlier intervention isnecessary.4The prevalence of RCD is currently unknown,but we believe that it might affect approximately 5% ofpatients with celiac disease. According to the EuropeanCeliac Disease working group, RCD can be subdividedinto types I and II, with phenotypically normal and aber-rant intraepithelial T lymphocytes in the small intestinalmucosa, respectively.69Intraepithelial T lymphocytes areconsidered aberrant when expressing cytoplasmic CD3,but lacking surface expression of the T-cell markersCD3, CD4, CD84and the T-cell receptor.70To discrimi-nate between RCD I and RCD II, a clinically validatedcut-off value of 20% aberrant intraepithelial T lympho-cytes, determined by analysis of small intestinal biopsysamples by flow cytometry, is used (Figure 2).70As flowcytometry cannot be performed in all medical centers,immunohistochemistry for CD3 and CD8 as a first-linescreening, before performing flow-cytometric analysis,in all patients diagnosed as having celiac disease and whoare above 50 years of age would also probably be helpful

in identifying patients with RCD II, but proper studiesare lacking.

Patients with RCD I have a less dismal prog nosiscompared with those diagnosed as having RCD II: the5-year survival rates are 8096% and 4458%, respec-tively.3,71,72The reason for this difference is the higherrisk of developing lymphoma in RCD II, as a conse-quence of clonal expansion and further transformationof aberrant intraepithelial T lymphocytes into EATL.3,4EATL occurs in more than half of patients with RCD IIwithin 46 years after RCD II diagnosis and is the maincause of death in this group of patients.3,71Developmentof EATL was also observed in patients with RCD I in a

single-center study, albeit less frequently than inpatients with RCD II (14%).72Furthermore, whereasRCD I can be treated effectively with prednisonewith or without azathioprine,71,73,74no standardizedapproach has yet been developed for RCD II, apartfrom aggressive nutritional support and strict adher-ence to a gluten-free diet.72,75In the past decade severalconventional and more experimental therapies havebeen evaluated to treat RCD II (Box 2), however thiscondition is usually resistant to any known therapy andtransition into EATL could not be prevented success-fully. Cladribine therapy76and autologous stem celltransplantation5might be successful, but long-term

results are awaited. Interleukin-15-blocking antibodies,which have been successfully used in the treatment ofrheumatoid arthritis, might be promising new thera-peutic alternatives, as this cytokine has a key role in thepathogenesis of RCD.77

Malignancies

Celiac disease is thought to be associated with anincreased risk of malignancies, in particular lympho-mas, but the risk currently estimated for this association,1.3-fold greater than that of the general population,78ismuch lower than that recorded in the 1970s and 1980s.79Earlier detection and treatment of celiac disease in the

Box 2| Treatment of complicated celiac disease

RCD I

Azathioprine 74

Azathioprine and prednisone 73

Budesonide 124

Infliximab 125

RCD II

Alemtuzumab 126

Autologous stem cell transplantation 5

Azathioprine and prednisone 73,74

Budesonide 124

Cladribine 76

Cyclosporine 127,128

Interleukin 10 129

Pentostatine 130

Mesenchymal stem cell infusion 131

Antibodies against interleukin 15 132

EATL

Allogenic stem cell transplantation133

Autologous stem cell transplantation 82,134

CHOP 83

Alemtuzumab and CHOP 135

Abbreviations: CHOP, cyclophosphamide, doxorubine, vincristine,

prednisone; EATL, enteropathy-associated T-cell lymphoma; RCD,

refractory celiac disease.

REVIEWS


8/11/2019 paper1 (11)


past two decades may have contributed to this decline.Whether continued gluten exposure is associated withthe high incidence of malignancies in patients with celiacdisease is widely debated, as many patients are not recog-nized as having the disease and are, therefore, untreated.A Finnish cohort study showed no additional risk formalignancies among adult patients with celiac diseasewho were diagnosed exclusively by serologic screeningand followed for almost 20 years.79

The principal malignancy associated with celiacdisease is EATL, which has an annual incidence of only0.51.0 cases per million people in Western countries.80Unexplained weight loss, abdominal pain, fever andnight sweating should alarm physicians of the pres-ence of an overt EATL. EATL can involve all areas ofthe small intestine, stomach and colon, being particu-larly frequent in the proximal jejunum. In some patientswith celiac disease, EATL may even occur outside thegastrointestinal tract, for example in the lungs, ribs andspleen, without abdominal pain.81EATL is one of themain causes of death in patients with adult-onset celiac

disease, with 2-year and 5-year overall survival rates of1520% and 820%, respectively.3,82This poor prog-nosis is mainly due to incomplete response to currentlyavailable therapies (Box 2), high rates of life-threateningcomplications such as perforation of the gut, and poornutritional conditions.75,83

Conclusions

Many factors have contributed to the increased preva-lence of celiac disease, which has emerged as a commonfood intolerance worldwide that can be diagnosed at allages. Growing insight into the clinical presentation ofceliac disease has resulted in novel diagnostic, prognosticand therapeutic dilemmas and highlights the importanceof considering the current diagnostic criteria of celiacdisease and its complications, as well as the evaluationand development of new treatment modalities.

Review criteria

A search of the MEDLINE database was performed

using the search terms celiac disease, gluten-

sensitive enteropathy, clinical presentation,symptoms, signs, diagnosis, serology, Marsh,

histopathology, histology, genetics, non-HLA-

genes, HLA-genes, environment, breastfeeding,

infections, screening, epidemiology, prevalence,

incidence, demographics, complications,refractory celiac disease, enteropathy associated

T-cell lymphoma, malignancies, non-Hodgkin

lymphomas and treatment. English-language full-text

articles and abstracts and a few non-English-languagepublications were considered. Articles included reviews,

meta-analyses, prospective and retrospective studies. No

publication date restrictions were applied.

1. Losowsky, M. S. A history of coeliac disease.Dig. Dis.26, 112120 (2008).

2. Wahab, P. J., Meijer, J. W. & Mulder, C. J.Histologic follow-up of people with celiac diseaseon a gluten-free diet: slow and incompleterecovery.Am. J. Clin. Pathol.118, 459463

(2002).3. Al-Toma, A., Verbeek, W. H., Hadithi, M.,von Blomberg, B. M. & Mulder, C. J. Survival inrefractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospectiveevaluation of single-centre experience. Gut56,13731378 (2007).

4. Cellier, C.et al.Refractory sprue, coeliacdisease, and enteropathy-associated T-celllymphoma. French Coeliac Disease Study Group.Lancet356, 203208 (2000).

5. Al-Toma, A.et al.Autologous hematopoietic stemcell transplantation in refractory celiac diseasewith aberrant T cells. Blood109, 22432249(2007).

6. Lohi, S.et al.Increasing prevalence of coeliacdisease over time.Aliment. Pharmacol. Ther.26,

12171225 (2007).7. Dub, C.et al.The prevalence of celiac diseasein average-risk and at-risk Western Europeanpopulations: a systematic review.Gastroenterology128(Suppl. 1), S57S67(2005).

8. Sollid, L. M.et al.Evidence for a primaryassociation of celiac disease to a par ticularHLA-DQ alpha/beta heterodimer.J. Exp. Med.169, 345350 (1989).

9. Mki, M.et al.Prevalence of celiac diseaseamong children in Finland. N. Engl. J. Med.348,25172524 (2003).

10. Kaukinen, K., Mki, M., Partanen, J.,Sievnen, H. & Collin, P. Celiac disease withoutvillous atrophy: revision of criteria called for. Dig.Dis. Sci.46, 879887 (2001).

11. Wahab, P. J., Crusius, J. B., Meijer, J. W. &Mulder, C. J. Gluten challenge in borderlinegluten-sensitive enteropathy.Am. J.Gastroenterol.96, 14641469 (2001).

12. Ludvigsson, J. F., Brandt, L. & Montgomery, S. M.Symptoms and signs in individuals with serology

positive for celiac disease but normal mucosa.BMC Gastroenterol.9, 57 (2009).13. Catassi, C.et al.Coeliac disease in the year

2000: exploring the iceberg. Lancet343,200203 (1994).

14. Virta, L. J., Kaukinen, K. & Collin, P. Incidenceand prevalence of diagnosed coeliac disease inFinland: results of effective case finding inadults. Scand. J. Gastroenterol.44, 933938(2009).

15. Rampertab, S. D., Pooran, N., Brar, P., Singh, P. &Green, P. H. Trends in the presentation of celiacdisease.Am. J. Med.119, 355.e9355.e14(2006).

16. Vilppula, A.et al.Increasing prevalence and highincidence of celiac disease in elderly people:a population-based study. BMC Gastroenterol.9,

49 (2009).17. Agostoni, C.et al.Complementary feeding:a commentary by the ESPGHAN Committee onNutrition.J. Pediatr. Gastroenterol. Nutr.46,99110 (2008).

18. Akobeng, A. K., Ramanan, A. V., Buchan, I. &Heller, R. F. Effect of breast feeding on risk ofcoeliac disease: a systematic review and meta-analysis of observational studies.Arch. Dis.Child.91, 3943 (2006).

19. Mylus, A.et al.Celiac disease revealed in 3% ofSwedish 12-year-olds born during an epidemic.

J. Pediatr. Gastroenterol. Nutr.49, 170176(2009).

20. Guandalini, S. The influence of gluten:weaning recommendations for healthy childrenand children at risk for celiac disease. Nestle

Nutr. Workshop Ser. Pediatr. Program.60,139151 (2007).

21. Plot, L. & Amital, H. Infectious associations ofCeliac disease.Autoimmun. Rev.8, 316319(2009).

22. Stene, L. C.et al.Rotavirus infection frequency

and risk of celiac disease autoimmunity in earlychildhood: a longitudinal study.Am. J.Gastroenterol.101, 23332340 (2006).

23. Plot, L.et al.Infections may have a protectiverole in the etiopathogenesis of celiac disease.

Ann. NY Acad. Sci.1173, 670674 (2009).24. Kondrashova, A.et al.Lower economic status

and inferior hygienic environment may protectagainst celiac disease.Ann. Med.40, 223231(2008).

25. Al-Toma, A.et al.Human leukocyte antigen-DQ2homozygosity and the development of refractoryceliac disease and enteropathy-associated T-celllymphoma. Clin. Gastroenterol. Hepatol.4,315319 (2006).

26. Bevan, S.et al.Contribution of the MHC regionto the familial risk of coeliac disease.J. Med.

Genet.36

, 687690 (1999).27. Garner, C. P.et al.Replication of celiac diseaseUK genome-wide association study results in aUS population. Hum. Mol. Genet.18,42194225 (2009).

28. Trynka, G.et al.Coeliac disease-associated riskvariants in TNFAIP3 and REL implicate alteredNF-kappaB signalling. Gut58, 10781083(2009).

29. Hunt, K. A.et al.Newly identified genetic riskvariants for celiac disease related to theimmune response. Nat. Genet.40, 395402(2008).

30. Romanos, J.et al.Analysis of HLA and non-HLAalleles can identify individuals at high risk forceliac disease. Gastroenterology137, 834840(2009).

REVIEWS


8/11/2019 paper1 (11)


31. Wolters, V. M.et al.The MYO9Bgene is a strongrisk factor for developing refractory celiacdisease. Clin. Gastroenterol. Hepatol.5,13991405 (2007).

32. Cummins, A. G. & Roberts-Thomson, I. C.Prevalence of celiac disease in the Asia-Pacificregion.J. Gastroenterol. Hepatol.24, 13471351(2009).

33. Catassi, C.et al.Why is coeliac disease endemicin the people of the Sahara? Lancet354,

647648 (1999).34. Sood, A., Midha, V., Sood, N., Avasthi, G. &Sehgal, A. Prevalence of celiac disease amongschool children in Punjab, North India.

J. Gastroenterol. Hepatol.21, 16221625(2006).

35. Bhattacharya, M., Dubey, A. P. & Mathur, N. B.Prevalence of Celiac disease in north Indianchildren. Indian Pediatr.46, 415417 (2009).

36. Malekzadeh, R., Sachdev, A. & Fahid, A. A.Coeliac disease in developing countries:Middle East, India and North Africa. Best Pract.Res. Clin. Gastroenterol.19, 351358 (2005).

37. Fasano, A.et al.Prevalence of celiac disease inat-risk and not-at-risk groups in the UnitedStates: a large multicenter study.Arch. Intern.Med.163, 286292 (2003).

38. Jacobson, D. L., Gange, S. J., Rose, N. R. &Graham, N. M. Epidemiology and estimatedpopulation burden of selected autoimmunediseases in the United States. Clin. Immunol.Immunopathol.84, 223243 (1997).

39. Green, P. H. R.et al.Characteristics of adult celiacdisease in the USA: results of a national survey.

Am. J. Gastroenterol.96, 126131 (2001).40. Hoffenberg, E. J.et al.A prospective study of the

incidence of childhood celiac disease.J. Pediatr.143, 308314 (2003).

41. Lurie, Y., Landau, D. A., Pfeffer, J. & Oren, R.Celiac disease diagnosed in the elderly.J. Clin.Gastroenterol.42, 5961 (2008).

42. Mki, M., Kallonen, K., Lhdeaho, M. L. &Visakorpi, J. K. Changing pattern of childhoodcoeliac disease in Finland.Acta Paediatr. Scand.

77, 408412 (1988).43. Tursi, A.et al.Prevalence and clinicalpresentation of subclinical/silent celiac diseasein adults: an analysis on a 12-year observation.Hepatogastroenterology48, 462464 (2001).

44. Bai, D., Brar, P., Holleran, S., Ramakrishnan, R. &Green, P. H. Effect of gender on themanifestations of celiac disease: evidence forgreater malabsorption in men. Scand. J.Gastroenterol.40, 183187 (2005).

45. Ferguson, A., Arranz, E. & OMahony, S. Clinicaland pathological spectrum of coeliac diseaseactive, silent, latent, potential. Gut34, 150151(1993).

46. Fabiani, E.et al.Dietary compliance in screening-detected coeliac disease adolescents.ActaPaediatr. Suppl.412, 6567 (1996).

47. Collin, P.et al.Coeliac disease-associateddisorders and survival. Gut35, 12151218(1994).

48. Giannotti, A.et al.Coeliac disease in Williamssyndrome.J. Med. Genet.38, 767768 (2001).

49. Walker-Smith, J. A., Guandalini, S., Schmitz, J.,Shmerling, D. H. & Visakorpi, J. K. Revisedcriteria for the diagnosis of celiac disease.Arch.Dis. Child.65, 909911 (1990).

50. Auricchio, R., Granata, V., Borrelli, M. &Troncone, R. Italian paediatricians approach tocoeliac disease diagnosis.J. Pediatr.Gastroenterol. Nutr.49, 374376 (2009).

51. Rostami, K.et al.Sensitivity of antiendomysiumand antigliadin antibodies in untreated celiacdisease: disappointing in clinical practice.Am. J.Gastroenterol.94, 888894 (1999).

52. Mohamed, B. M.et al.The absence of a mucosallesion on standard histological examinationdoes not exclude diagnosis of celiac disease.Dig. Dis. Sci.53, 5261 (2008).

53. Feighery, C.et al.Diagnosis of gluten-sensitiveenteropathy: is exclusive reliance on histologyappropriate? Eur. J. Gastroenterol. Hepatol.10,919925 (1998).

54. Hopper, A. D.et al.What is the role of serologictesting in celiac disease? A prospective, biopsy-

confirmed study with economic analysis. Clin.Gastroenterol. Hepatol.6, 314320 (2008).55. Lewis, N. R. & Scott, B. B. Meta-analysis:

deamidated gliadin peptide antibody and tissuetransglutaminase antibody compared asscreening tests for coeliac disease.Aliment.Pharmacol. Ther.31, 7381 (2009).

56. Rostom, A.et al.The diagnostic accuracy ofserologic tests for celiac disease: a systematicreview. Gastroenterology128(Suppl. 1),S38S46 (2005).

57. Coll in, P.et al.Selective IgA deficiency andcoeliac disease. Scand. J. Gastroenterol.27,367371 (1992).

58. Cataldo, F.et al.IgG(1) antiendomysium and IgGantitissue transglutaminase (anti-tTG)antibodies in coeliac patients with selective IgA

deficiency. Working Groups on Celiac Disease ofSIGEP and Club del Tenue. Gut47, 366369(2000).

59. Kaukinen, K., Partanen, J., Mki, M. & Collin, P.HLA-DQ typing in the diagnosis of celiac disease.

Am. J. Gastroenterol.97, 695699 (2002).60. Karinen, H.et al.HLA genotyping is useful in the

evaluation of the risk for coeliac disease in the1st-degree relatives of patients with coeliacdisease. Scand. J. Gastroenterol.41,12991304 (2006).

61. Chang, M. & Green, P. H. Genetic testing beforeserologic screening in relatives of patients withceliac disease as a cost containment method.

J. Clin. Gastroenterol.43, 4350 (2009).62. Mulder, C. J. J.et al.Celiac disease: guidelines

of the Dutch medical association.

Kwaliteitsinstituut [online], http://www.cbo.nl/Downloads/303/rl_coeliakie_08.pdf/(2008).63. Hopman, E. G., le Cessie., S.,

von Blomberg, B. M. & Mearin, M. L. Nutritionalmanagement of the gluten-free diet in youngpeople with celiac disease in The Netherlands.

J. Pediatr. Gastroenterol. Nutr.43, 102108(2006).

64. Casellas, F.et al.Factors that impact health-related quality of life in adults with celiacdisease: a multicenter study. World J.Gastroenterol.14, 4652 (2008).

65. Whitaker, J. K., West, J., Holmes, G. K. &Logan, R. F. Patient perceptions of the burden ofcoeliac disease and its treatment in the UK.

Aliment. Pharmacol. Ther.29, 11311136(2009).

66. Lerner, A. New therapeutic strategies for celiacdisease.Autoimmun. Rev.9, 144147 (2010).67. Askling, J.et al.Cancer incidence in a

population-based cohort of individualshospitalized with celiac disease or dermatitisherpetiformis. Gastroenterology123,14281435 (2002).

68. Silano, M.et al.Delayed diagnosis of coeliacdisease increases cancer risk. BMCGastroenterol.7, 8 (2007).

69. [No authors listed] When is a coeliac a coeliac?Report of a working group of the UnitedEuropean Gastroenterology Week in Amsterdam,2001. Eur. J. Gastroenterol. Hepatol.13,11231128 (2001).

70. Verbeek, W. H.et al.Flow cytometricdetermination of aberrant intra-epithelial

lymphocytes predicts T-cell lymphomadevelopment more accurately than T-cellclonality analysis in refractory celiac disease.Clin. Immunol.126, 4856 (2008).

71. Rubio-Tapia, A.et al.Clinical staging andsurvival in refractory celiac disease: a singlecenter experience. Gastroenterology136,99107 (2009).

72. Malamut, G.et al.Presentation and long-termfollow-up of refractory celiac disease:

comparison of type I with type II.Gastroenterology136, 8190 (2009).73. Goerres, M. S.et al.Azathioprine and

prednisone combination therapy in refractorycoeliac disease.Aliment. Pharmacol. Ther.18,487494 (2003).

74. Maurio, E.et al.Azathioprine in refractorysprue: results from a prospective, open-labelstudy.Am. J. Gastroenterol.97, 25952602(2002).

75. Verbeek, W. H.et al.Novel approaches in themanagement of refractory coeliac disease.Expert Rev. Clin. Immunol.4, 205219 (2008).

76. Al-Toma, A.et al.Cladribine therapy in refractoryceliac disease with aberrant T cells. Clin.Gastroenterol. Hepatol.4, 13221327 (2006).

77. Ferrari-Lacraz, S.et al.Targeting IL-15 receptor-

bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development andprogression in murine collagen-inducedarthritis.J. Immunol.173, 58185826 (2004).

78. Card, T. R., West, J. & Holmes, G. K. Risk ofmalignancy in diagnosed coeliac disease:a 24-year prospective, population-based, cohortstudy.Aliment. Pharmacol. Ther.20, 769775(2004).

79. Lohi, S.et al.Malignancies in cases withscreening-identified evidence of coeliacdisease: a long-term population-based cohortstudy. Gut58, 643647 (2009).

80. Catassi, C., Bearzi, I. & Holmes, G. K.Association of celiac disease and intestinallymphomas and other cancers.Gastroenterology128(Suppl. 1), S79S86

(2005).81. Verbeek, W. H.et al.Incidence of enteropathy-associated T-cell lymphoma: a nation-widestudy of a population-based registry in TheNetherlands. Scand. J. Gastroenterol.43,13221328 (2008).

82. Bishton, M. J. & Haynes, A. P. Combinationchemotherapy followed by autologous stem celltransplant for enteropathy-associated T celllymphoma. Br. J. Haematol.136, 111113(2007).

83. Daum, S.et al.Intestinal non-Hodgkinslymphoma: a multicenter prospective clinicalstudy from the German Study Group onIntestinal non-Hodgkins Lymphoma.J. Clin.Oncol.21, 27402746 (2003).

84. Vancikov, Z.et al.The serologic screening for

celiac disease in the general population (blooddonors) and in some high-risk groups of adults(patients with autoimmune diseases,osteoporosis and infertility) in the Czechrepublic. Folia Microbiol. (Praha)47, 753758(2002).

85. Henker, J., Lsel, A., Conrad, K., Hirsch, T. &Leupold, W. Prevalence of asymptommaticcoeliac disease in children and adults in theDresden region of Germany [German]. Dtsch.Med. Wochenschr.127, 15111515 (2002).

86. West, J.et al.Seroprevalence, correlates, andcharacteristics of undetected coeliac diseasein England. Gut52, 960965 (2003).

87. Bingley, P. J.et al.Undiagnosed coeliac diseaseat age seven: population based prospectivebirth cohort study. BMJ328, 322323 (2004).

REVIEWS

http://www.cbo.nl/Downloads/303/rl_coeliakie_08.pdf/http://www.cbo.nl/Downloads/303/rl_coeliakie_08.pdf/http://www.cbo.nl/Downloads/303/rl_coeliakie_08.pdf/http://www.cbo.nl/Downloads/303/rl_coeliakie_08.pdf/

8/11/2019 paper1 (11)

10/10NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY VOLUME 7 | APRIL 2010 | 213

88. Corazza, G. R.et al.The smaller size of thecoeliac iceberg in adults. Scand. J.Gastroenterol.32, 917919 (1997).

89. Castao, L.et al.Three-year follow-up of healthynewborns for celiac disease diagnosis.J. Pediatr.Gastroenterol. Nutr.36, 536 (2003).

90. Catassi, C.et al.The coeliac iceberg in Italy. Amulticentre antigliadin antibodies screening forcoeliac disease in school-age subjects.ActaPaediatr. Suppl.412, 2935 (1996).

91. Johnston, S. D., Watson, R. G., McMillan, S. A.,Sloan, J. & Love, A. H. Prevalence of coeliacdisease in Northern Ireland. Lancet350, 1370(1997).

92. Riestra, S., Fernndez, E., Rodrigo, L., Garcia, S.& Ocio, G. Prevalence of coeliac disease in thegeneral population of northern Spain. Strategiesof serologic screening. Scand. J. Gastroenterol.35, 398402 (2000).

93. Ivarsson, A.et al.High prevalence ofundiagnosed coeliac disease in adults:a Swedish population-based study.J. Intern.Med.245, 6368 (1999).

94. Carlsson, A. K., Axelsson, I. E., Borulf, S. K.,Bredberg, A. C. & Ivarsson, S. A. Serologicalscreening for celiac disease in healthy2.5-year-old children in Sweden. Pediatrics107,

4245 (2001).95. Schweizer, J. J., von Blomberg, B. M.,Bueno-de-Mesquita, H. B. & Mearin, M. L.Coeliac disease in The Netherlands. Scand. J.Gastroenterol.39, 359364 (2004).

96. Csizmadia, C. G., Mearin, M. L.,von Blomberg, B. M., Brand, R. &Verloove-Vanhorick, S. P. An iceberg of childhoodcoeliac disease in the Netherlands. Lancet353,813814 (1999).

97. Gomez, J. C.et al.Prevalence of celiac diseasein Argentina: screening of an adult population inthe La Plata area.Am. J. Gastroenterol.96,27002704 (2001).

98. Gandolfi, L.et al.Prevalence of celiac diseaseamong blood donors in Brazil.Am. J.Gastroenterol.95, 689692 (2000).

99. Remes-Troche, J. M.et al.Celiac disease couldbe a frequent disease in Mexico: prevalence oftissue transglutaminase antibody in healthyblood donors.J. Clin. Gastroenterol.40,697700 (2006).

100. Bhattacharya, M., Dubey, A. P. & Mathur, N. B.Prevalence of celiac disease in north Indianchildren. Indian Pediatr.46, 415417 (2009).

101. Shahbazkhani, B.et al.High prevalence ofcoeliac disease in apparently healthy Iranianblood donors. Eur. J. Gastroenterol. Hepatol.15,475478 (2003).

102. Imanzadeh, F.et al.Celiac disease in childrenwith diarrhea is more frequent than previouslysuspected.J. Pediatr. Gastroenterol. Nutr.40,309311 (2005).

103. Dahan, S., Slater, P. E., Cooper, M., Brautbar, C. &

Ashkenazi, A. Coeliac disease in the Rehovot-Ashdod region of Israel: incidence and ethnicdistribution.J. Epidemiol. Community Health38,5860 (1984).

104. Khuffash, F. A.et al.Coeliac disease amongchildren in Kuwait: difficulties in diagnosis andmanagement. Gut28, 15951599 (1987).

105. Tatar, G.et al.Screening of tissuetransglutaminase antibody in healthy blooddonors for celiac disease screening in theTurkish population. Dig. Dis. Sci.49, 14791484(2004).

106. Ertekin, V., Selimoglu, M. A., Kardas, F. &Aktas, E. Prevalence of celiac disease in Turkish

children.J. Clin. Gastroenterol.39, 689691(2005).107. Mankai, A.et al.Celiac disease in Tunisia:

serological screening in healthy blood donors.Pathol. Biol. (Paris)54, 1013 (2006).

108. Ben Hariz, M.et al.Prevalence of celiac diseasein Tunisia: mass-screening study inschoolchildren. Eur. J. Gastroenterol. Hepatol.19,687694 (2007).

109. Hovell, C. J.et al.High prevalence of coeliacdisease in a population-based study fromWestern Australia: a case for screening? Med. J.

Aust.175, 247250 (2001).110. Cook, H. B.et al.Adult coeliac disease:

prevalence and clinical significance.J. Gastroenterol. Hepatol.15, 10321036 (2000).

111. Rizzello, C. G.et al.Highly efficient gluten

degradation by lactobacilli and fungal proteasesduring food processing: new perspectives forceliac disease.Appl. Environ. Microbiol.73,44994507 (2007).

112. Gianfrani, C.et al.Transamidation of wheat flourinhibits the response to gliadin of intestinalT cells in celiac disease. Gastroenterology133,780789 (2007).

113. Pinier, M.et al.Polymeric binders suppressgliadin-induced toxicity in the intestinalepithelium. Gastroenterology136, 288298(2009).

114. Mitea, C.et al.Efficient degradation of gluten bya prolyl endoprotease in a gastrointestinalmodel: implications for coeliac disease. Gut57,2532 (2008).

115. Gass, J., Bethune, M. T., Siegel, M., Spencer, A. &

Khosla, C. Combination enzyme therapy forgastric digestion of dietary gluten in patients withceliac sprue. Gastroenterology133, 472480(2007).

116. Tye-Din, J. A.et al.The effects of ALV003 pre-digestion of gluten on immune response andsymptoms in celiac disease in vivo. Clin.Immunol. doi:10.1016/j.clim.2009.11.001.

117. De Angelis, M.et al.VSL#3 probiotic preparationhas the capacity to hydrolyze gliadin polypeptidesresponsible for celiac sprue. Biochim. Biophys.

Acta1762, 8093 (2006).118. Kelly, P. C.et al.Safety, tolerability and effects on

intestinal permeability of larazotide acetate inceliac disease: results of a phase IIB 6-weekgluten-challenge clinical trial [abstract M2048].Gastroenterology136(Suppl. 1), A-474 (2009).

119. Molberg, O.et al.T cells from celiac diseaselesions recognize gliadin epitopes deamidatedin situ by endogenous tissue transglutaminase.Eur. J. Immunol.31, 13171323 (2001).

120. Xia, J.et al.Cyclic and dimeric gluten peptideanalogues inhibiting DQ2-mediated antigenpresentation in celiac disease. Bioorg. Med.Chem.15, 65656573 (2007).

121. Keech, C. L., Dromey, J., Chen, Z.,Anderson, R. P. & McCluskey, J. P. Immunetolerance induced by peptide immunotherapy inan HLA Dq2-dependent mouse model of glutenimmunity [abstract 355]. Gastroenterology136(Suppl. 1), A-57 (2009).

122. Summers, R. W., Elliott, D. E., Urban, J. F. Jr,Thompson, R. & Weinstock, J. V. Trichuris suistherapy in Crohns disease. Gut54, 8790(2005).

123. Salvati, V. M.et al.Recombinant humaninterleukin 10 suppresses gliadin dependentT cell activation in ex vivo cultured coeliacintestinal mucosa. Gut54, 4653 (2005).

124. Brar, P.et al.Budesonide in the treatment ofrefractory celiac disease.Am. J. Gastroenterol.102, 22652269 (2007).

125. Costantino, G.et al.Treatment of life-threatening type I refractory coeliac diseasewith long-term infliximab. Dig. Liver Dis.40,7477 (2008).

126. Verbeek, W. H., Mulder, C. J. & Zweegman, S.Alemtuzumab for refractory celiac disease.

N. Engl. J. Med.355, 13961397 (2006).127. Longstreth, G. F. Successful treatment ofrefractory sprue with cyclosporine.Ann. Intern.Med.119, 10141016 (1993).

128. Wahab, P. J., Crusius, J. B., Meijer, J. W., Uil, J. J.& Mulder, C. J. Cyclosporin in the treatment ofadults with refractory coeliac diseasean openpilot study.Aliment. Pharmacol. Ther.14,767774 (2000).

129. Mulder, C. J., Wahab, P. J., Meijer, J. W. &Metselaar, E. A pilot study of recombinanthuman interleukin-10 in adults with refractorycoeliac disease. Eur. J. Gastroenterol. Hepatol.13, 11831188 (2001).

130. Dray, X.et al.A severe but reversible refractorysprue. Gut55, 12101211 (2006).

131. Garca-Castro, J.et al.Mesenchymal stem cells

and their use as cell replacement therapy anddisease modelling tool.J. Cell Mol. Med.12,25522565 (2008).

132. Baslund, B.et al.Targeting interleukin-15 inpatients with rheumatoid arthritis:a proof-of-concept study.Arthritis Rheum.52,26862692 (2005).

133. Regelink, J. C.et al.Disappointing outcome ofallogeneic hematopoietic SCT in two EATLpatients. Bone Marrow Transplant.doi:10.1038/bmt.2009.250.

134. Al-Toma, A.et al.Disappointing outcome ofautologous stem cell transplantation forenteropathy-associated T-cell lymphoma. Dig.Liver Dis.39, 634641 (2007).

135. Gallamini, A.et al.Alemtuzumab (Campath-1H)and CHOP chemotherapy as first-line treatment

of peripheral T-cell lymphoma: results of a GITIL(Gruppo Italiano Terapie Innovative nei Linfomi)prospective multicenter trial. Blood110,23162323 (2007).

REVIEWS

Documents

paper1 (11)