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Symposium 1: Joint BAPEN and British Society of Gastroenterology Symposium on ‘Coeliac disease: basics and controversies’ Coeliac disease in the twenty-first century

Conference on ‘Malnutrition matters’

Published online by Cambridge University Press:  03 June 2009

William Dickey
William Dickey*
Affiliation:
Altnagelvin Hospital, LondonderryBT47 6SB, UK
*
Corresponding author: William Dickey, fax +44 2871 611218, email wildickey@aol.com
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Abstract

Coeliac disease (CD), traditionally perceived as a rare childhood condition presenting with malabsorption, is instead an autoimmune multisystem disorder usually presenting in adulthood, affecting ⩾1% of the population and linked to the genetic expression of human leucocyte antigens (HLA) DQ2 and DQ8. Presentation occurs most often in the 40–60 years age-group, but potentially at any age. Symptoms attributable to the gut or to malabsorption may be mild, non-specific or absent; under one-third of patients have diarrhoea and almost half are overweight. Histological diagnosis no longer requires small intestine villous atrophy. The Marsh classification recognizes increased intraepithelial lymphocytes and crypt hyperplasia with intact villi as part of the gluten enteropathy spectrum, while some individuals have more subtle abnormalities identified only on electron microscopy. Serological testing for CD autoantibodies (to endomysium and tissue transglutaminase) has revolutionized diagnosis, shifting the process towards primary care. However, a substantial number of patients with CD are seronegative, particularly those without villous atrophy. The autoantibody to endomysium may be produced before histological change. The immune response to transglutaminase is crucial to the disease process. An exciting new development is the link between antibodies to organ-specific transglutaminases and clinical presentation; transglutaminases 2 (gut), 3 (skin) and 6 (nervous system). Negative testing for CD does not preclude its development later and HLA testing may allow ‘once and for all’ exclusion. In conclusion, an increasing proportion of patients with CD do not meet the ‘classic’ picture of malabsorption, positive serological testing and villous atrophy. Insisting on all these criteria for diagnosis will result in under diagnosis.

Keywords

Coeliac diseaseDiagnosisEnteropathyAutoantibodies
Type
Research Article
Information
Proceedings of the Nutrition Society , Volume 68 , Issue 3 , August 2009 , pp. 234 - 241
Copyright
Copyright © The Author 2009

Abbreviations:
CD

coeliac disease

EmA

endomysium antibodies

HLA

human leucocyte antigen

tTG

tissue tranglutaminase

tTGA

tTG antibodies

VA

villous atrophy

Coeliac disease (CD) is an autoimmune disease triggered in genetically-susceptible individuals by the ingestion of the gluten proteins of wheat, barley and rye. There is a strong association with other autoimmune disorders and, genetically, with the human leucocyte antigen (HLA) DQ2 and DQ8 alleles. The autoimmune processes of CD are directed against tissue transglutaminase (tTG) 2, resulting in the formation of autoantibodies to tTG (tTGA) and endomysium (EmA), which can be detected in the serum. Villous atrophy (VA) and an excess of lymphocytes are typical histological findings in the proximal small intestine (duodenum, jejunum). The present review covers the epidemiology, clinical presentations and diagnosis of CD with a particular focus on recent literature.

Pathogenesis of coeliac disease

CD shares with other autoimmune disorders a close association with HLA-linked genes; >90% of patients with CD are DQ2 positive, with most of the rest carrying DQ8 alleles(Reference Sollid and Lie1). Peptide sequences of dietary gluten, which are resistant to protease activity in the gut, are deamidated by tTG(Reference Molberg, Flaete and Jensen2). Deamidated gluten peptides form complexes with HLA-DQ and trigger a T-cell-mediated inflammatory response(Reference Tollefsen, Arentz-Hansen and Fleckenstein3). While this response has direct effects on the small bowel mucosa, CD is a multisystem disorder affecting potentially any organ system and there is evidence that autoantibodies directed against tTG as part of the process have consequences elsewhere in the body.

Epidemiology

Failed and delayed diagnosis of CD used to be common, as clinicians failed to recognize the various manifestations of CD and their potential to commence at any age(Reference Dickey and McConnell4–Reference Gasbarrini, Ciccocioppo and De Vitis6).

Far from being a rare condition, population-screening studies indicate not only that CD affects approximately 1% of many populations with European ancestry, including those in the Americas and Australasia(Reference Mearin, Ivarsson and Dickey7), but also that it is as common in the Middle East(Reference Shahbazhkhani, Malekzadeh and Sotoudeh8, Reference Shamir, Lerner and Shinar9) and the Indian subcontinent(Reference Sood, Midha and Sood10). Most patients present for the first time with symptoms in adulthood, with peak onset of symptoms in the 40–60 years age-group(Reference Dickey and McMillan11). Onset of symptoms and diagnosis are often in later life; in one Italian study 4% of patients were diagnosed after the age of 65 years(Reference Gasbarrini, Ciccocioppo and De Vitis6).

Clinical presentations

Potential clinical presentations can be categorized into three main groups, although some symptoms have more than one basis:

  1. 1. malabsorption, e.g. diarrhoea, abdominal pain, flatus–flatulence, weight loss, anaemia, osteomalacia, osteoporosis;

  2. 2. gut dysmotility, e.g. reflux, dysphagia, dyspepsia, constipation;

  3. 3. autoimmunity, e.g. dermatitis herpetiformis, neuropathy, ataxia.

BMI and gastrointestinal symptoms

While the patient with CD was traditionally considered to be underweight, with symptoms attributable to malabsorption such as diarrhoea, flatus and abdominal distension, recent studies report that 28–39% of patients are overweight (BMI ⩾25 kg/m2) at presentation(Reference Dickey and Kearney12–Reference Murray, Watson and Clearman14). In the author's own experience fewer than one-third of patients report diarrhoea as a presenting symptom(Reference Dickey and McMillan11). In a US study the percentage of patients diagnosed with CD who presented with diarrhoea fell from 73% pre-1993 to 43% after 1993(Reference Lo, Sano and Lebwohl15). Traditionally, some patients with CD were wrongly diagnosed as having irritable bowel syndrome; new guidelines from the UK National Institute for Health and Clinical Excellence(Reference Dalrymple and Bullock16) recommend that coeliac serology should be checked in all patients suspected of having irritable bowel syndrome. The possibility of dual pathology should be considered in patients with CD who do present with diarrhoea. There is an association between CD and inflammatory bowel disease(Reference Yang, Chen and Scherl17) and the author's own approach is to perform colonoscopy in patients with CD presenting with altered bowel habit after the age of 40 years to exclude coincidental colon neoplasia(Reference Dickey18). Diarrhoea that does not rapidly respond to gluten exclusion should prompt a search for small bowel neoplasia and ulcerative jejunitis complicating CD(Reference Brousse and Meijer19). There are also links with exocrine pancreatic insufficiency, which may be easily detected using faecal elastase assays(Reference Leeds, Hopper and Hurlstone20), with small intestinal bacterial overgrowth(Reference Tursi, Brandimarte and Giorgetti21) and with microscopic colitis(Reference Olesen, Eriksson and Bohr22).

Many patients with CD present with symptoms more typically associated with the upper gastrointestinal tract, including reflux, nausea, dysphagia and epigastric pain. These symptoms are related in part to gut dysmotility, which is well documented in CD, although the mechanism is uncertain(Reference Usai, Bassotti and Usai Satta23). The constipation that is paradoxically seen in some patients with CD is probably explained on the same basis. Patients with these symptoms are more likely to undergo upper gastrointestinal endoscopy as a first-line investigation. While duodenal biopsy as a routine at every endoscopy is not cost effective, it should be performed in patients having endoscopy for anaemia who have a family history of CD and considered for those with dyspeptic symptoms that have not responded to conventional acid suppressants. A proportion of patients with VA have endoscopic abnormalities in the duodenum (scalloped folds; fold loss; mosaic, grooved or nodular mucosa; erosions; visible vessels), which should prompt biopsy if seen(Reference Dickey24).

Anaemia and B-vitamin deficiency

Fe deficiency

Fe, whether derived from animal (haem) or plant sources, is absorbed in the duodenum and jejunum and Fe deficiency is to be expected as a result of the proximal enteropathy of CD. In the author's experience approximately one-third of new patients present with Fe-deficiency anaemia without gastrointestinal symptoms(Reference Dickey and McMillan11), while Fe deficiency has been reported in 33% of men and 19% of women at diagnosis(Reference Harper, Holleran and Ramakrishnan25). The Fe-deficiency anaemia of CD often does not respond to supplements until a gluten-free diet is started. When bleeding sources are excluded by upper gastrointestinal endoscopy and colon investigation, CD is confirmed in 10% of all patients with Fe-deficiency anaemia(Reference Dickey, Kenny and McMillan26) and in 20% of individuals identified as having Fe deficiency by pre-blood-donation screening(Reference Ferguson and Dickey27).

Folate deficiency

Like Fe, folic acid is absorbed in the proximal small bowel and deficiency in patients with CD is common, affecting 12% of a recent US study cohort(Reference Harper, Holleran and Ramakrishnan25). Confusion may be caused when Fe and folate deficiency co-exist, resulting in normalization of the mean cell volume. An increase in erythrocyte distribution width as the result of a dimorphic population of erythrocytes allows differentiation of both mixed Fe and folate deficiency and Fe and vitamin B12 deficiency from the anaemia of chronic disease. It has been proposed that an increased erythrocyte distribution width should prompt testing for CD(Reference Sategna Guidetti, Scaglione and Martini28).

Vitamin B12 deficiency

Although the primary site of vitamin B12 absorption is the terminal ileum, vitamin B12 deficiency is common in CD, affecting 5–41% of adult patients(Reference Harper, Holleran and Ramakrishnan25, Reference Dahele and Ghosh29, Reference Dickey30). The reduction in serum vitamin B12 level associated with CD is much less than that typically seen in autoimmune gastritis (true pernicious anaemia).

Homocysteine

Folic acid and vitamin B12, along with vitamin B6 and riboflavin, are needed for the metabolism of homocysteine, which is widely considered to be a risk factor for heart disease and stroke. Higher levels of homocysteine have been found in untreated patients with CD compared with healthy controls, with normalization after recovery of VA(Reference Dickey, Ward and Whittle31). Raised homocysteine may account for the prevalence of stroke and cardiac disease in patients with CD, which is comparable with rates in controls, despite generally lower cholesterol levels(Reference West, Logan and Card13).

Other haematological problems

Hyposplenism is well recognized as a complication of CD. It may be identified by the presence of Howell-Jolly bodies, acanthocytes and target cells on blood film analysis, raised platelet counts and ‘pitted’ erythrocytes(Reference Di Sabatino, Rosado and Cazzola32). A recent English study has reported a twofold risk of pneumococcal infection in patients with CD(Reference Thomas, Wotton and Yeates33). Accordingly, screening for hyposplenism in CD seems appropriate, with relevant vaccinations where they are not routinely administered. Dapsone, used in the management of dermatitis herpetiformis, is associated with methaemoglobinaemia, haemolytic anaemia and neutropenia.

Liver disease

A substantial minority of patients with CD have raised serum levels of aspartate and alanine transaminase on liver function testing, which settle after gluten exclusion(Reference Dickey, McMillan and Collins34–Reference Novacek, Miehsler and Wrba36). Serological testing for CD should be part of the initial investigation of raised serum transaminases. Where liver biopsies have been performed in this situation they show changes of non-specific hepatitis and specific liver investigation is usually not required. While raised serum transaminases are usually an incidental finding, there have been patients with severe liver disease requiring transplantation in whom CD has been identified and appropriate treatment has reversed liver failure(Reference Kaukinen, Halme and Collin37).

However, it is important to differentiate this finding from specific autoimmune liver diseases that have been linked with CD. Patients with primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis all have an increased prevalence of CD(Reference Ludvigsson, Elfström and Broomé38). Diagnostic confusion may arise from raised serum tTGA levels in primary liver disease with no evidence of CD. tTGA assays may give a false positive reaction in liver fibrosis(Reference Vecchi, Folli and Donato39).

Bone and joint disease

Traditionally, CD presenting with overt malabsorption was associated with osteomalacia and rickets, manifest as bone pain and reduced serum Ca and phosphate. This disorder is now seldom seen and the widespread availability of dual-energy X-ray absorptiometry scanning has shown that osteoporosis–osteopenia is by far the commonest bone disorder of CD, affecting 20–50% of patients at diagnosis(Reference Meyer, Stravropolous and Daimond40–Reference Kemppainen, Kroger and Janatuinen42). Aetiological factors include Ca and vitamin D malabsorption and secondary hyperparathyroidism, but serum bone-specific autoantibodies have been described(Reference Sugai, Cherñavsky and Pedreira43).

In most cases osteoporosis is asymptomatic and picked up by dual-energy X-ray absorptiometry screening. More important than the prevalence of osteoporosis is its clinical impact, and recent case–control studies suggest that fracture risk remains low in absolute terms, ranging from no risk to only a twofold increase compared with controls(Reference Vestergaard and Mosekilde44–Reference Ludvigsson, Michaelsson and Ekbom46). Guidelines produced for the British Society of Gastroenterology recommend that all adults with CD should have dual-energy X-ray absorptiometry at diagnosis(Reference Scott, Gaywood and Scot47), but the authors of the guidelines have recently questioned this approach(Reference Lewis and Scott48). The merit of screening patients with osteoporosis for CD is uncertain. There is no increase in CD prevalence among post-menopausal women(Reference González, Sugai and Gomez49), although the yield in other groups may be higher. Where reduced bone density is identified in CD there is improvement with gluten exclusion(Reference Pazianas, Butcher and Subhani50, Reference Sategna-Guidetti, Grosso and Grosso51).

Arthritis and joint pain are well described in CD(Reference Hernandez and Green52). Of specific rheumatological disorders only Sjogren's syndrome, which shares DQ2 and DQ8 haplotypes, appears to be associated with CD, with a prevalence of 5–15% among patients with Sjogren's syndrome(Reference Iltanen, Collin and Korpela53, Reference Luft, Barr and Martin54). The finding of tTGA in patients with other forms of arthritis may be a non-specific finding(Reference Picarelli, Di Tola and Sabbatella55).

Skin disease

Dermatitis herpetiformis, an intensely-itchy blistering rash characteristically affecting the buttocks, elbows and knees is the typical skin lesion of CD and was the first and best-described extraintestinal manifestation of gluten sensitivity. Clinical characteristics of 264 US patients have recently been published(Reference Alonso-Llamazares, Gibson and Rogers56), showing an excess of male patients in contrast to the female preponderance in most CD series. Patients presenting with dermatitis herpetiformis appear to have a lower risk of complications such as osteoporosis(Reference Abuzakouk, Barnes and O'Gorman57). Dapsone is highly effective in achieving skin remission but has no effect on other organ involvement(Reference Nino, Ciacci and Delfino58). Gluten exclusion may take months to control the rash, but will allow Dapsone withdrawal within 18 months in most cases(Reference Nino, Ciacci and Delfino58).

Infertility and miscarriage

For some years a link between CD and infertility or recurrent miscarriage has been reported(Reference Stazi and Mantovani59), but studies were small, making interpretation difficult. In a recent large case–control study that used primary-care data for >1500 women with CD and 7700 matched controls it was found that while crude fertility rates are almost identical, age-specific fertility rates show that women with CD have lower fertility when younger but higher fertility when older compared with women without CD(Reference Tata, Card and Logan60). This age-related increase in relative fertility is independent of treatment for CD. Furthermore, risks of caesarean section (OR 1·33) and miscarriage (rate ratio 1·31) are moderately higher in women with CD, but risks of assisted birth, breech birth, pre-eclampsia, postpartum haemorrhage, ectopic pregnancy, stillbirth and termination are similar. However, the effects of socio-economic or educational advantage rather than a true disease effect could not be excluded. A comparison of the outcomes of children of mothers with CD before and after diagnosis and treatment has shown that rates of intrauterine growth retardation, low birth weight, pre-term birth and caesarean section are higher in the before diagnosis and treatment group, suggesting a beneficial effect of gluten exclusion(Reference Ludvigsson, Montgomery and Ekbom61).

Neurological disease

Neurological manifestations of CD are extensively described in the literature, and again may be the primary presentation with little or no gastrointestinal symptomatology(Reference Luostarinen, Pirttila and Collin62). Some, but not all, studies report an excess of epilepsy among patients with CD and vice versa(Reference Luostarinen, Dastidar and Collin63–Reference Ranua, Luoma and Auvinen65). A specific syndrome of bilateral occipital cerebral calcification, partial seizures and CD is rare, with <200 patients reported in the literature and geographically localized to Italy, Spain and Argentina(Reference Gobbi66). Better-established associations are with peripheral neuropathy(Reference Ludvigsson, Olsson and Ekbom67, Reference Hadjivassiliou, Gibson and Davies-Jones68) and cerebellar ataxia(Reference Hadjivassiliou, Gibson and Davies-Jones68–Reference Burk, Bosch and Muller70). CD has been found in 4% of ninety migraine sufferers compared with 0·4% of 236 controls(Reference Gabrielli, Cremonini and Fiore71). Conversely, the prevalence of headache in 176 patients with CD has been reported to be 46% compared with 29% for controls(Reference Cicarelli, Della Rocca and Amboni72). Both studies indicate that gluten exclusion brings about an improvement.

Neurological problems were traditionally assumed to be a result of malabsorption, but nutritional deficiencies have not been consistently demonstrated and neurological symptoms do not respond to supplementation(Reference Muller, Donnelly and Smith73). Specific autoantibodies directed at components of the nervous system have been described in patients with CD(Reference Alaedini, Green and Sander74, Reference Tursi, Giorgetti and Iani75).

An English study has suggested that neurological disease as a result of gluten sensitivity may exist without enteropathy(Reference Hadjivassiliou, Grunewald and Davies-Jones76). Patients thus affected may lack tTGA and EmA and have normal duodenal biopsies by conventional criteria. These findings question the reliance on small bowel histology to confirm a diagnosis of CD.

Diagnosis of coeliac disease

The most important step in diagnosis is to think of the possibility, which requires awareness of the many possible presentations of CD. In addition, suspicion should be higher where there is a family history of CD and in patients with a number of autoimmune conditions that are associated through HLA with an increased prevalence of CD; as well as liver disease and Sjogren's syndrome already mentioned, these conditions include type 1 diabetes mellitus(Reference Mahmud, Murray and Kudva77), autoimmune thyroid disease(Reference Ch'ng, Biswas and Benton78) and Addison's disease(Reference Betterle, Lazzarotto and Spadaccino79). There is an increased prevalence of CD in Down syndrome(Reference Bonamico, Mariani and Danesi80). Upper gastrointestinal endoscopy, for whatever indication, in these patients should include duodenal biopsies as a matter of routine, as well as in patients with anaemia and with visible stigmata of VA in the duodenum(Reference Dickey24). It is important that an adequate gluten intake is maintained until serology and biopsies are obtained. Empirical reduction in gluten intake, on the advice of family, friends, alternative practitioners and even physicians may result not only in false negative serology but also normalization of duodenal histology.

Serological tests

Serological testing, using EmA and tTGA, has revolutionized the diagnosis of CD by allowing investigation by non-gastroenterologists who are more likely to observe its manifestations beyond the gut. As a result, the majority of cases of CD in the author's practice are identified initially by general practitioners(Reference Dickey and McMillan11). Detection of EmA requires an operator with a microscope to check for antibody fluorescence, making the test labour-intensive and subjective and providing at best a semi-quantitative result. In contrast, tTGA assays typically use ELISA, which can provide a quantitative and non-operator-dependent result by automated spectrophotometry. Recently, kits have become commercially available that allow rapid near-patient testing for tTGA. These products include the Biocard (Ani Biotech Oy, Vantaa, Finland), which measures IgA human tTGA on a finger-prick blood droplet, and the Stick CD1 (Operon SA, Saragoza, Spain), which uses serum to test for IgG and IgA human tTGA. Their performance is similar to lab-based assays and the ease of use of the Biocard offers the opportunity for testing in the community by paramedical staff such as district nurses(Reference Korponay-Szabo, Szabados and Pusztai81).

Sensitivity of serological tests

Research data to date in relation to the performance of lab-based IgA EmA and tTGA for CD has been summarized recently(Reference Hill82). While some studies report sensitivity and specificity approaching 100%, these studies are often performed in research facilities with a much higher CD:non-CD sera than that seen in clinical practice, which will tend to improve performance. A further problem is that the criteria used for diagnosis of CD vary from study to study, with some excluding milder grades of VA and Marsh I and II lesions (for details of the Marsh classification of lesions, see later and Marsh(Reference Marsh83)). Research from routine clinical practice indicates that serology has 80–90% sensitivity(Reference Hopper, Hadjivassiliou and Hurlstone84, Reference Dickey, McMillan and Hughes85) for Marsh III histology. Both EmA and tTGA have lower sensitivities for milder degrees of VA(Reference Rostami, Kerckhaert and Tiemessen86, Reference Cataldo, Marino and Ventura87). Patients with non-VA gluten sensitivity (Marsh I, Marsh II) are more likely to test negative for tTGA and EmA(Reference Sinclair, Saas and Turk88). Approximately 2·5% of patients with CD have selective IgA deficiency, representing a tenfold increase in prevalence over the general population(Reference Tursi, Brandimarte and Giorgetti89). These patients cannot produce IgA EmA and tTGA. While some centres measure total IgA routinely with coeliac antibodies, quantitative tests such as tTGA will show very low or zero levels in cases of selective IgA deficiency(Reference Wahab, Crusius and Meijer90) and this situation should prompt IgG class tTGA and EmA measurements. Antigliadin antibody assays, previously widely used in diagnosis, are now considered to be obsolete in most centres because of poor sensitivity and specificity(Reference Hill82). Recently, serological testing for antibodies to deamidated antigliadin has been shown to have similar performance to tTGA assays, but further studies are needed(Reference Volta, Granito and Fiorini91).

False positive tissue transglutaminase antibodies

tTGA may be found in liver disease(Reference Vecchi, Folli and Donato39), arthritis(Reference Picarelli, Di Tola and Sabbatella55) and end-stage heart failure(Reference Peracchi, Trovato and Longhi92) without evidence of CD. These false positive results may be a result of increased non-specific tTG activity in inflammation occurring in any organ system. A high percentage of children with tTGA will seroconvert without dietary restriction(Reference Simell, Kupila and Hoppu93), suggesting a temporary phenomenon in some cases. Currently, there are no data as to whether patients with high tTGA and no evidence of CD are at greater risk of its development later.

No such thing as false positive endomysium antibodies?

Approximately 10% of patients with EmA do not have VA on duodenal biopsy(Reference Dickey, Hughes and McMillan94). However, some of these patients have Marsh I lesions, and of the remainder most will develop VA on follow-up biopsy or will respond symptomatically to a trial of dietary gluten exclusion(Reference Mohamed, Feighery and Coates95, Reference Grodzinsky, Fälth-Magnusson and Högberg96). Furthermore, electron microscopy studies of duodenal biopsies from patients who are EmA-positive but with no abnormality under light microscopy(Reference Sbarbati, Valletta and Bertini97) show reductions in microvilli height, reduction in microvilli density and branching and enterocyte damage; again, progression to VA is observed during follow-up. It is likely that EmA positivity can precede the development of histological lesions and should be considered as a true manifestation of gluten sensitivity rather than a false positive finding.

Organ-specific transglutaminase antibodies

Recent work suggests that gluten sensitivity may be associated with autoantibodies against organ-specific transglutaminases. While the autoantigen in patients with coeliac enteropathy is transglutaminase 2, sera from patients with dermatitis herpetiformis react in addition to transglutaminase 3, which is epidermal in origin(Reference Sárdy, Kárpáti and Merkl98). Similarly, sera from patients with gluten-related cerebellar ataxia have activity against the neuronal isoenzyme transglutaminase 6(Reference Hadjivassiliou, Aeschlimann and Strigun99). If these autoantibodies are shown to be specific for gluten-related disease, they may have value in diagnosis, particularly where intestinal involvement is minimal or undetectable.

Duodenal histology in coeliac disease

The demonstration of characteristic inflammatory and atrophic abnormalities of the proximal small intestine in duodenal biopsies remains central to the diagnosis of CD, both to support the diagnosis where serology is positive and to confirm the diagnosis in patients with characteristics suggesting CD despite negative EmA or tTGA. Traditionally, VA was required to make a diagnosis of CD, but in 1992 a spectrum of changes consistent with gluten enteropathy were described by Marsh(Reference Marsh83). In the Marsh I lesion the villi are intact but infiltrated by intraepithelial lymphocytes (>30/100 enterocytes), in Marsh II this lymphocytosis is accompanied by hyperplasia of the crypts, while the ‘classic’ CD lesion, showing these changes plus atrophy of the villi, is termed Marsh III(100). Milder degrees of gluten enteropathy are clinically significant. Relatives of patients with CD who have Marsh I lesions identified through family screening are more likely to have symptoms, anaemia and reduced bone density than those with normal histology(Reference Esteve, Rosinach and Fernández-Bañares101). However, the characteristic finding of Marsh I enteropathy, intraepithelial lymphocytosis, poses a greater problem in relation to specificity for gluten enteropathy, as it is seen in 1–2% of all duodenal biopsy samples(Reference Kakar, Nehra and Murray102, Reference Mahadeva, Wyatt and Howdle103), and may be a result of other gut pathologies, including other dietary protein intolerance, parasites, Helicobacter pylori gastritis, bacterial overgrowth and inflammatory bowel disease(Reference Brown, Mino-Kenudson and Deshpande104). Support for gluten sensitivity is provided by family history of CD, by positive serology in a minority of cases(Reference Dickey, Hughes and McMillan94, Reference Mohamed, Feighery and Coates95) and by determination of HLA-DQ2 and -DQ8 status. In the absence of these factors and with no alternative diagnosis a trial of gluten exclusion may be warranted.

The recent description of ‘microenteropathy’, with changes associated with gluten sensitivity visible only under electron microscopy(Reference Sbarbati, Valletta and Bertini97), suggests that the spectrum of gluten-sensitive enteropathy extends even further than Marsh I.

Conclusions

CD is a common autoimmune disorder affecting multiple organ systems. Patients may present at any age and with wide-ranging symptoms. Serological testing using EmA and tTGA has revolutionized diagnosis, while duodenal biopsy remains a mainstay of baseline investigation, although histological changes may be more subtle than VA. However, there needs to be awareness of the limitations of serological testing with a well-documented false negative rate and, in the case of tTGA, false positives, while there is increasing evidence of gluten-sensitive disease with minimal or not readily demonstrable gut involvement. Autoantibodies against organ-specific transglutaminases may have a role to play in diagnosis. The only certainty is the association with HLA-DQ2 and -DQ8. In the future, diagnosis of CD may be made by weighing up various factors (clinical, serological and histological), with none individually necessary for the diagnosis.

Acknowledgements

The author is an unpaid member of the Medical Advisory Council of Coeliac UK.

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