AGA Technical Review on Celiac Sprue - UAlberta

AGA Technical Review on Celiac Sprue

The literature review and the recommendations therein were prepared for the American Gastroenterological Association (AGA)Clinical Practice and Practice Economics Committee. The paper was approved by the Committee on September 23, 2000, and bythe AGA governing board on November 12, 2000.

This report is a comprehensive review of the currentstate of knowledge of celiac sprue, its pathogenesis,

clinical presentation, diagnosis, treatment, and outcome.

DefinitionCeliac sprue may be defined as a condition in

which there is an abnormal proximal small intestinalmucosa that improves morphologically on treatmentwith a gluten-free diet and relapses when gluten isreintroduced. The condition termed celiac sprue may alsobe called celiac disease or gluten-sensitive enteropathy. Itwas previously termed nontropical sprue, celiac syn-drome, idiopathic steatorrhea, or primary malabsorption.The condition has a genetic predisposition.

Dermatitis herpetiformis (DH) is a related disorder inwhich there is an itchy blistering skin eruption thatfrequently affects the knees, elbows, buttocks, and back,with deposition of granular immunoglobulin (Ig) A atthe dermoepidermal junction of the skin including areasnot involved with the rash. Patients with DH have adegree of small intestinal enteropathy, which improveson gluten withdrawal.

Historical AspectsAretaeus the Cappadocian described the condition

in the second century A.D., noting that “if diarrhea doesnot proceed from a slight cause of only one or two daysduration and if, in addition, the patient’s general systembe debilitated by atrophy of the body, the celiac sprue ofa chronic nature is formed.”

Samuel Gee described the condition as we know it in1887. He noted the disease affected all ages. It is ofinterest that he thought that “to regulate the food wasthe main part of treatment.” He recognized that “if thepatient can be cured at all it must be by means of thediet.” He described “a child who was fed upon a quart ofthe best Dutch mussels daily, throve wonderfully butrelapsed when the season for mussels was over. Nextseason he could not be prevailed upon to take them. Thisis an experiment I have not yet been able to repeat, butif the patient can be cured at all, it must be by means ofthe diet.”

In 1924, Haas described his treatment of celiac sprue.He thought it logical to try a banana diet in childrenwith celiac sprue following his successful treatment ofanorexia with this regime. He excluded bread, crackers,potatoes, and cereals. Bananas were gradually added tothe diet usually from the fourth or eighth day. Thetreatment was continued indefinitely.

This dietary treatment of the condition continued wellinto the 1950s. In the Netherlands during World War IIthere had been a scarcity of cereals, and bread in partic-ular. Dicke, a Dutch pediatrician, observed that celiacsprue diminished remarkably during this shortage.1 Heobserved that children with celiac disease quickly re-lapsed after Swedish planes dropped bread into the Neth-erlands. This helped Dicke to realize that wheat wastoxic to individuals with celiac sprue. Dicke and cowork-ers proceeded to show that wheat flour was the offendingsubstance and that the toxicity resided in the glutenfraction.1,2

Early diagnosis was made on clinical grounds. The latedescription of the histology was due to the presumptionthat the abnormal changes seen at autopsy were post-mortem artifacts. In 1954, Paulley et al. reported thehistology of jejunal mucosa obtained operatively.3 Shinerand Royer independently developed methods for per-forming a biopsy on the duodenum, followed by Crosby,who developed the Crosby capsule.

EpidemiologyCeliac sprue is mostly a disease of Europe and

those countries to which Europeans have emigrated, in-cluding North America and Australia. Celiac sprue wasthought to affect 1:1500 throughout Europe with pock-ets of greater frequency. Hin et al.4 recently used sero-logic screening followed by diagnostic small intestinalbiopsy to show that in the United Kingdom the trueprevalence may be 1:300. In Southern and Northern

Abbreviations used in this paper: AGA, antigliadin antibody; DH,dermatitis herpetiformis; EMA, antiendomysial antibody; IEL, intraepi-thelial lymphocyte; tTG, tissue transglutaminase.

© 2001 by the American Gastroenterological Association0016-5085/01/$35.00

doi:10.1053/gast.2001.24056

GASTROENTEROLOGY 2001;120:1526–1540

Ireland, the prevalence has recently been revised to 1:150of the population. In the United States, where the prev-alence of celiac sprue has always been lower than inEurope, a recent screening of blood from 2000 blooddonors found a prevalence of raised endomysial antibod-ies of 1:250.

Celiac sprue occurs in non-Caucasoids, although theprevalence is apparently much lower. It has been re-ported in Indians, Arabs, Hispanics, Israeli Jews, Su-danese, and people of Cantonese extraction. It occursrarely in those of Afro-Caribbean origin.

Gender Incidence

The female to male ratio is generally accepted tobe 2:1, although some have suggested it may be moreequal.

Twin Studies

Concordance in identical twins is well described.Although discordance has been reported in several cases,after prolonged follow-up in the majority of cases, thediscordant twin has gone on to develop the condition.

Mortality

Before the introduction of the gluten-free diet,the outlook for individuals with celiac sprue was poor,with published mortality rates varying between 10% and30%. After the introduction of the gluten-free diet,mortality rates fell markedly with a published rate of0.4% in one series.5 Previous evidence suggested that themortality rate was twice that of a matched control pop-ulation,6 although there are no recent studies to supportthis.7

PathologyCeliac sprue affects the mucosa of the proximal

small intestine with damage gradually decreasing inseverity towards the distal small intestine, although insevere cases, the lesion extends to the ileum. The degreeof proximal damage varies greatly depending on theseverity of the disease. The proximal damage may be verymild in “silent” cases with little or no abnormalitydetectable histologically in the mid jejunum. Abnormal-ities of the gastric and rectal mucosa may be observed insome cases.8

The best biopsy specimens of the proximal smallintestinal mucosa are obtained using a suction guillotinebiopsy capsule. If available, it may be useful to examinethe biopsy specimens using a dissecting microscope. Thisallows observers to distinguish between normal villousmucosa and flat biopsy specimens that are present in

celiac sprue with degrees of abnormality falling betweenthese 2 categories. Normal mucosa exhibits digitate villi,leaf forms, and ridges. The villi vary in size, shape, andheight but are usually 3 times taller than they are wide(Figure 1A). Convolutions, which are normal, are longridges that can be regarded as villi that have fused andbuckled. There are different appearances of the smallintestinal mucosa, depending on whether subjects residein temperate or tropical climates. Fully convoluted ap-pearances occur in more than 5% of normal subjects intropical areas. Infants exhibit broad leaves and villi, withfinger-shaped villi rarely present.

The small intestinal mucosa in celiac sprue may be flatand featureless and may present a flat mucosal patterncaused by interaction of deep depressions leaving ele-vated mounds. Each mound has 8–40 crypt openings. Ifa dissecting microscope is available, examination of bi-opsy specimens by dissecting microscopy is of value inassessing specimens for patchiness of mucosal abnormal-ity, particularly in DH, where a patchy lesion is morecommon.

The characteristic histologic appearance of small in-testinal mucosa from a patient with untreated celiac

Figure 1. Photomicrograph of the histology of a small intestinal bi-opsy specimen from (A) a normal subject and (B) a subject withuntreated celiac sprue.

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sprue classically exhibits a flat mucosa with reduction inthe normal villous height to crypt depth ratio frombetween 5:1 and 3:1 (Figure 1B). The total thickness ofthe mucosa may be increased because of crypt hyperplasiaand infiltration of the lamina propria by plasma cells andlymphocytes. Surface enterocyte height is reduced. Cryptmitotic activity is normally confined to the lower third of

the crypt, but in celiac sprue this activity may be in-creased, although the histologic appearance of the cryptseems normal. The histologic differential diagnosis willbe between celiac sprue, tropical sprue, eosinophilic en-teritis, and Crohn’s disease. Confirmation of the diagno-sis will include improvement in the histologic abnormal-ities on the small intestinal biopsy specimen as well assymptomatic improvement with a gluten-free diet.There is generalized lymphocytic infiltration of the epi-thelium that may extend into the crypts.

The time taken for the cells to migrate from the cryptto the surface is reduced from between 3 and 5 tobetween 1 and 2 days. The number of intraepitheliallymphocytes (IELs) in relation to the number of surfacecell enterocytes is increased in patients with active dis-ease. Chronic inflammatory cells infiltrate the small in-testinal mucosa in untreated celiac sprue. There are in-creased numbers of plasma cells in the lamina propriaand lymphocytes in the surface epithelium. Most IELsexpress the common leukocyte antigen CD3, 70% ex-press the suppressor/cytotoxic phenotype CD8, 5%–10%express the helper/inducer CD4 phenotype, and 20% ofthe cells are CD31, CD42, and CD82. There is also anincrease in the number of IELs expressing the moreprimitive g/d T-cell receptor in the untreated condition.

Figure 2. A skin blister on the elbow of a subject with dermatitisherpetiformis.

Figure 3. Endoscopic photograph of reduced folds in the second partof the duodenum in a patient with untreated sprue.

Figure 4. Radiologic appearance of a small bowel barium follow-through from a patient with untreated celiac sprue.

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Types of Mucosal Lesions

The mucosal lesion has been classed into 5 types.9

Type 0 preinfiltration lesion. Five percent of pa-tients with DH have small intestinal biopsy specimensthat appear normal but secrete antigliadin antibody.

Type 1 infiltrative lesion. There is a normal mu-cosal architecture but with an increased number of IELs.This lesion occurs in 40% of patients with DH and 10%of first degree relatives of patients with celiac sprue.9

This lesion is not associated with any symptoms or signsof malabsorption and intestinal permeability studies arenormal.

Type 2 hyperplastic lesion. In addition to theincreased IELs, there is an increase in crypt depth with-out a reduction in villous height. Gluten challenge caninduce these changes, which are seen in 20% of untreatedDH patients and in celiac patients.

Type 3 destructive lesion. This is the classicalceliac lesion. It is found in 40% of DH patients and10%–20% of first degree relatives of celiac patients, and,despite marked mucosal changes, many individuals areasymptomatic and therefore classified as subclinical. Thislesion is characteristic of, but not diagnostic for, celiacsprue and can also be seen with severe giardiasis, infantilefood sensitivities, graft versus host disease, chronic isch-emia of the small intestine, tropical sprue, Ig deficien-cies, and other immune deficiencies and allograft rejec-tion.

Type 4 hypoplastic lesion. This can be consideredthe end-stage lesion in a very small group of patients whoare unresponsive to gluten withdrawal and may developmalignant complications. There is deposition of collagenin the mucosa and submucosa (collagenous sprue), whichis usually unresponsive to treatment with steroids, im-munosuppressive agents, or chemotherapy.

Categories of Celiac Sprue

The increased awareness of the genetic basis forceliac sprue, disease associations, and changes in patternsof presentation is consistent with the development ofnew techniques for screening, which have produced alarge number of individuals who cannot be classifiedsimply by the presence or absence of celiac sprue. Largescale population screening studies suggest that the diag-nosed celiac population may represent the tip of aniceberg of undiagnosed cases. Those not diagnosed withthe condition will fall into one of the following catego-ries.

Undiagnosed celiac sprue. These individualshave classical mucosal lesions and are symptomatic buthave not been diagnosed.

Silent celiac sprue. Individuals in this grouphave characteristic morphologic changes in the smallintestinal biopsy in the absence of clinical signs andsymptoms. If only the proximal small intestine is af-fected, there may be physiologic compensation by nor-mal small bowel, although it is likely that symptomsmight be manifest if the gluten load is increased.

Latent celiac sprue. Those individuals who havegenetic susceptibility to the disease but do not manifestclinical or histologic evidence of the disorder. It is likelythat the timing and quality of gluten load, possiblycombined with other environmental triggers or intercur-rent illness, may be a factor in the age of presentation inthese individuals.

True normals. These individuals lack genetic sus-ceptibility to the condition and do not manifest eitherhistologic or clinical symptoms at any stage. However,there is a separate condition in which there is an IgE-based allergy to gluten or other wheat proteins.

Characterization of Toxic CerealPeptidesClassification of Cereal Protein

The precise structure of the part of gluten, whichcauses the damage in celiac sprue, remains unclear.Wheat grains have 3 major constituents that are sepa-rated by milling: the outer husk or bran, the germ, andthe endosperm or white flour, which constitutes 70%–72% of the whole grain by weight and contains the toxiccomponents. The storage proteins of cereals fall into 2major groups: the ethanol-soluble fraction termed prola-mins and the glutenins. Prolamins from the differentcereals are termed gliadins from wheat, secalins from rye,hordeins from barley, avenins from oats, and zeins fromceliac nontoxic maize.

Wheat proteins are divided into classes according totheir solubility characteristics: gliadins are soluble in40%–90% ethanol, and glutenins are insoluble in neu-tral aqueous solution, saline, or ethanol. The gliadinsmay be further subdivided into alpha, beta, gamma, andomega subfractions either according to their relativeelectrophoretic mobility, or alpha, beta, and omega ac-cording to their N-terminal amino acid sequences. Themolecular masses of gliadins range from 32 to 58 kilo-daltons.

After Dicke’s discovery that the toxic fraction of wheatresided in the endosperm or flour fraction of wheat,Frazer10 purified and separated wheat protein peptidesafter physiologic digestion of the proteins. He showedthat the majority of these peptides were toxic to celiacpatients in remission. Hekkens et al.11 went on to show


that a-gliadin exacerbated celiac sprue in vivo and morerecently all 4 gliadin subfractions were shown to exacer-bate celiac sprue both in vitro and in vivo.

Kagnoff et al.12,13 reported that A-gliadin shares an 8amino acid sequence homology, in a span of 12 aminoacids, with an identical pentapeptide with the 54-kilo-dalton Elb protein of human adenovirus 12, an adenovi-rus usually isolated from the gastrointestinal tract. Oth-ers were unable to find a correlation between the presenceof celiac sprue and serum antibody titers to the adeno-virus 12 protein. However, while the adenovirus hypoth-esis is attractive and has analogies to theories regardingthe pathogenesis of autoimmune disease, it is no longergenerally accepted.

Glutamine comprises 35% of the amino acids in gli-adin and may play a central role in its toxicity. Evidencefor this lies in the fact that complete deamidation ofglutamine removes the toxic properties; however, partialdeamidation has been found to increase the sensitivity ofcloned gluten-sensitive T cells to these proteins. Se-quences of A-gliadin, a major component of a-gliadin,were published by Kasarda et al.14 Subsequent to this,the toxicity of various synthetic peptide sequences fromA-gliadin has been assessed using celiac small bowelbiopsy organ culture techniques. Toxicity has beenshown using peptide sequences corresponding to residues3-24, 25-55, 31-55, and 1-30 of A-gliadin.15 Gjertson etal.16 reported that a peptide corresponding to amino acidresidues 31-49 was recognized by CD41 T cells obtainedfrom the peripheral blood of a patient with celiac spruewhen presented by the HLA-DQ2 heterodimer. Sturgesset al.17 subsequently reported that this same peptideexacerbated celiac sprue in vivo after intraduodenal in-fusion and using a multiple small intestinal biopsy tech-nique.

Molberg et al.18 have recently shown that tissue trans-glutaminase (tTG) causes selective deamidation of glutenproteins, which increases their stimulating effect on glu-ten-sensitive T cells obtained from the small intestine ofpatients with celiac sprue. It has been postulated thatthis results in neoepitopes in wheat proteins, which arethen involved in the disease pathogenesis.

Genetics

Celiac sprue is an HLA-associated condition, theprimary association being with major histocompatibilitycomplex class II alleles DQA1*0501 and DQB1*0201.19

This HLA-DQ2 allelic combination is found in 98% ofceliac patients from Northern Europe. The association ofceliac sprue with DR3 is thought to be through linkagedisequilibrium with DQ2. In Southern Europe, DQ2 isalso the major susceptibility genotype, being present in

92% of celiac patients, where it is inherited either in ciswith DR3 or in trans in DR5, DR7 heterozygotes (i.e.,the DQA and B alleles are encoded on different chromo-somes). In Southern Europe and Israel, there is anothersmaller group of affected subjects who carry HLA-DQ8in association with DR4.20

Despite the strong HLA association, there is onlyabout 30%–50% concordance for celiac sprue in HLAidentical siblings, compared with concordance approach-ing 100% in monozygotic twins. The risk in first degreerelatives is between 10% and 20%.21,22 It should also berecognized that 25% of the “normal” Northern Europeanpopulation carries DQ2. Thus other genetic influences,probably non-HLA linked, may be required for develop-ment of the disease. Two genome-wide searches for suchgenes have been undertaken,23,24 but as yet no conclusiveresults have emerged.

The susceptibility to celiac sprue therefore seems to begenetically determined by possession of certain HLA-DQalleles together with 1 or more non-HLA genes. Linkageanalysis was used to study T-cell receptor a/b and g/dgenes using microsatellite markers, in 21 multiply af-fected pedigrees. No evidence of linkage was found.25

Pathogenesis

The known antigen, that is wheat gluten, and theHLA predisposition are brought together in the cur-rently accepted theory of pathogenesis. It has been pro-posed that gluten-sensitive T cells recognize gluten-derived peptide epitopes when presented in associationwith DQ2.26 Evidence suggests that upon activation,these CD41 gluten-sensitive T cells develop a Th1/Th0type inflammatory response,27 which produces the ob-served mucosal damage. The exact epitope(s) within glu-ten remain unknown, although there is mounting evi-dence for the role of a 19 mer peptide from theN-terminal region of A-gliadin, a constituent of gluten,corresponding to amino acid residues 31-49, comprisingone of several possible toxic epitopes. This peptide hasbeen shown to cause histologic features of celiac sprue byin vitro organ culture28 and in vivo challenge studies.17

It has also been shown to bind to DQ2 molecules29,30 andstimulate T cells derived from the peripheral blood ofceliac patients, when presented in association withDQ2.16

Clinical FeaturesInfancy and Childhood

The classical presentation of celiac sprue occursafter weaning and introduction of cereals into the diet.There is failure to thrive associated with apathy, pallor,


anorexia, and muscle wasting. There is generalized hy-potonia and abdominal distention with the child passingsoft, bulky, clay-colored, offensive stools. Very youngchildren may present with vomiting, which is ofteneffortless, of large volume, and usually associated withabdominal distention and little or no diarrhea. Abdom-inal pain may be so severe that a laparotomy is under-taken because of a mistaken diagnosis of intestinal ob-struction. In some cases, this pain is caused byconstipation. Retardation of motor activity has beenobserved. Presenting symptoms are extremely varied andinclude rectal prolapse, although this is more common incystic fibrosis. Intussusception can occasionally occur.

Older children tend to have more varied symptom-atology and may present with anemia or failure to grownormally. Rickets may occur, particularly in Asian chil-dren. Unexplained short stature is an indication for per-forming a small intestinal biopsy, even when gastroin-testinal symptoms are mild or absent. After diagnosisand introduction of a gluten-free diet, there is often asignificant increase in height and weight.

Gastrointestinal symptoms may date from birth in25% of children, whereas more than half become symp-tomatic in the first 6 months of life. After the age of 6months, the development of symptoms may be caused bythe introduction of cereals to the diet during weaning.The notable exception to this is Sweden, where infantfeeding practices have returned to the early introductionof gluten to infants within the first weeks of life. Laterintroduction of large amounts of gluten had previouslybeen associated with an upsurge of cases presented dur-ing infancy. It has been suggested that celiac sprueoccurs predominantly in infants who had not been breastfed, although this has not been substantiated.

Adult Life

Adult and adolescent patients with celiac spruemay present with symptoms in almost any hospital de-partment (Table 1). Diarrhea is the main presentingfeature, whereas those with constitutional disturbancessuch as lassitude, loss of weight, glossitis, and symptomsof anemia form another group. A small group presentbecause of abnormal psychological or psychiatric symp-toms, including schizophrenia. There may be presenta-tion with problems related to osteomalacia, includingspontaneous fractures, and myopathy, skin complaints,bleeding diathesis, or infertility.

Many individuals have long-standing ill health formany years and, never having had severe symptoms,accept this as normal. Abdominal pain occurs in 5% ofcases. Aphthous stomatitis may be the sole presentingsymptom, and therefore celiac sprue should be excluded

in cases of severe unexplained recurrent mouth ulcer-ation.

The stress of an operation or infection can occasionallyinduce severe diarrhea. Pregnancy may precipitate mac-rocytic or iron-deficiency anemia and the onset of unex-plained diarrhea. After pregnancy, the symptoms mayabate and the diagnosis may be missed.

Presenting symptoms in many patients with celiacsprue are nonspecific and therefore a high diagnosticsuspicion should be aroused with minor abnormalitiessuch as hematological or biochemical profiles, includingpersistent transaminitis. The finding of a mild unex-plained macrocytic anemia with persistently low serumor red cell folate should suggest further investigation andmay lead to a diagnosis of celiac sprue. A previousdiagnosis of celiac sprue in childhood can be overlookedby both the patient and doctor only to become a sourceof symptoms in adult life. Clinicians should thereforeexplore possible childhood disturbances such as shortstature, anemia, or rickets.

There is a 10% prevalence among first degree rela-tives. Certain symptoms, in particular lassitude, may beattributed to psychiatric illness. Glossitis, angular sto-matitis, and cheilosis may be present. Nausea and vom-iting are common, particularly during episodes of diar-rhea in children. There may be anorexia, althoughappetite may be increased in some patients and poly-phagia has been reported. Abdominal distention is com-mon and often associated with flatulence.

Table 1. Clinical and Laboratory Features Encountered inCeliac Sprue

Anemic iron deficiencyAnemic folate deficiencyAnorexiaBone painDepressionDiarrheaFinger clubbingHyposplenismInfertilityLassitudeNausea/vomitingRecurrent abdominal painRecurrent apthous stomatitisRecurrent miscarriagesShort statureWeight lossRaised antibody titers to gliadin, reticulin, endomysium, and tissue

transglutaminasePossible hypoalbuminemia, low B12, and prolonged prothrombin

timePathologic fracturesEchymosesCheilosis


Symptoms of cramp and tetany may occur, usuallyassociated with low serum calcium or magnesium levels.Bowel disturbance is the most frequent problem, usuallyin the form of loose stools. The motion may be paler thannormal, sometimes offensive, occasionally frothy, anddifficult to flush away. Bowel frequency varies, but iscommonly 3–4 times a day and rarely more than 8 timesa day. Normally formed and colored stools do not pre-clude the diagnosis. Steatorrhea may be present eventhough the patient has stools with a normal appearance.Physicians should remember to enquire specifically abouta subject’s stool because patients with long-standingbowel disturbance frequently make no complaint. Inaddition, clinicians should examine patients’ stools toavoid any problem pertaining to the patients’ powers ofobservation. It has been reported that 10% of patientssuffer incontinence complicating nocturnal diarrhea. Arecent study has shown that 10% of patients sufferingfrom irritable bowel syndrome were subsequently foundto be suffering from celiac sprue.4 Constipation has beenreported to occur in 10% of cases, although this may bean underestimate.

Abdominal pain is uncommon and may indicate theneed for investigation to exclude intra-abdominal pathol-ogy complicating celiac sprue, in particular such condi-tions as volvulus, intussception, mesenteric adenitis, cho-lelithiasis, peptic ulceration, and pancreatitis.

Scurvy and epistaxis have been reported, and occasion-ally there may be bleeding into the skin and subcutane-ous tissue. This may reflect vitamin K deficiency.

Osteomalacia, rickets, or bone pain lead to the diag-nosis of celiac sprue in an appreciable number of subjectsreflecting low calcium and vitamin D absorption. Symp-toms of rickets and osteomalacia are frequently insidiousin onset and may become severe before they are recog-nized.

Dermatitis HerpetiformisThis skin disorder is associated with celiac sprue

because some degree of gluten-sensitive enteropathy iscommon to both conditions. It is characterized by anitchy papular, vesicular eruption. This rash is usuallysymmetrical and located on the elbows, knees, buttocks,sacrum, face, neck, trunk, and occasionally within themouth. The predominant symptoms are itching andburning, which may be so severe as to cause pain. Rup-ture of the blisters results in a rapid relief of symptoms.

The earliest abnormality consists of a small erythem-atous macule 2–3 mm in diameter, which quickly de-velops into a papule. Small vesicles then seem to coalesce.Scratching causes them to rupture, dry up, and possibly

leave an area of pigmentation and scarring. The vesiclesappear tense and shiny (Figure 2), containing a clear fluidthat clouds as the lesion progresses and may be tingedwith blood in rapidly growing blisters. Solitary vesiclesmay occur. The lesions tend to occur in crops, althoughall stages may be evidenced at one time. The blisters take7–10 days to evolve. The rash was found to respond tosulphapyridine and subsequently to dapsone.

Associated symptoms are the same as for celiac sprue.These include lassitude, diarrhea, abdominal pain, anddistention. The degree of malabsorption found in pa-tients with DH is less than that found in celiac sprue.Only 10% of patients have symptoms attributable tomalabsorption, although almost 100% have a histologi-cally abnormal jejunal mucosa.14 There is a slight pre-dominance in males.

The diagnosis depends on the demonstration of gran-ular IgA in the skin in areas not affected by blistering.This granular deposition occurs at the dermoepidermaljunction, distinguishing DH from linear IgA deposition,a separate condition not associated with celiac sprue.

The majority of patients with DH have an abnormalsmall intestinal mucosa, reaching nearly 100% whenseveral biopsy specimens are taken, suggesting that thelesion is patchy. Some patients have apparently normalsmall intestinal biopsy specimens but increased lympho-cyte counts in the epithelium (Marsh type 1), the num-bers of which fall towards normal after treatment with agluten-free diet. The degree of mucosal change maydepend on the amount of gluten ingested, as well asindividual sensitivity. The exact relationship of the glu-ten-sensitive enteropathy found in patients with DH tothat found in celiac sprue remains unclear.

The treatment of DH is dapsone at a dose of 50–100mg/day, although a smaller dosage may be used, whichdoes not affect the small intestinal enteropathy. Patientsshould be advised to take a gluten-free diet as, in manycases, this results in a significant improvement after6–12 months, permitting reduction in the dose of dap-sone required to control the rash. The diet may evencompletely eliminate the need for dapsone. However, thefull benefits are not seen for months or years, resulting inmany patients discontinuing their gluten-free diets.

Physical Signs

Children with celiac sprue are usually irritableand miserable. Adults may suffer depression, paranoia,Korsakov’s syndrome, and neurasthenia. Most individu-als experience an improved outlook on life when theyexclude gluten from their diet.


Celiac patients are generally shorter than their peers.However, a height of over 1.8 m does not preclude thediagnosis. Both adults and children frequently experi-ence weight loss, with an average of 12 kg in one series.31

Children may exhibit delayed eruption of teeth, andhypoplasia of the dental enamel has been described. Alow-grade fever associated with anemia may be encoun-tered and may be a manifestation of a complication suchas lymphoma. Clubbing and koilonychia have both beenreported. Edema and ascites may rarely be present re-flecting hypoproteinemia. Frequently there is abdominaldistention making the abdomen feel like dough.

The menarche is, on average, delayed 1 year in indi-viduals subsequently shown to have celiac disease. Am-enorrhea lasting more than 3 months unrelated to preg-nancy occurs in one third of women of childbearing age.The average age of the menopause in untreated celiacsprue is 45 compared with 53 years on a gluten-free diet.Many celiac patients are relatively infertile and sponta-neous abortion occurs in 18% of pregnancies comparedwith 9% of patients on a gluten-free diet. Recurrentmiscarriage may be a presenting symptom.

Men may experience a reduction in potency. Bothfertility and normal sperm counts are restored by agluten-free diet. A delay in puberty and development ofsecondary sexual characteristics may occur in untreatedceliac patients. These abnormalities revert to normalafter prolonged treatment.

Hematologic and BiochemicalAbnormalities

The characteristic blood picture is of a mild di-morphic anemia, with severe anemia occurring uncom-monly. The blood film may exhibit target cells, Howell–Jolly bodies, siderocytes, irregular and crenated cells,Heinz bodies, microspherocytes, acanthocytes, occasionalerythroblasts, with possible evidence of hyposplenism.The serum levels of iron and folic acid are usually low. Amacrocytic megaloblastic anemia may occasionally occur.Examination of the bone marrow usually reveals mega-loblastic erythropoiesis when iron and folic acid areinvariably reduced and 14% of patients have a B12 levelthat is lower than controls. Iron and folic acid should betherapeutically replaced, and possibly B12, although lev-els normally rise without replacement.

DiagnosisSmall Intestinal Biopsy

The diagnosis may be suspected on clinicalgrounds and as a result of various screening tests. How-ever, for confirmation, it is mandatory to proceed to a

small intestinal biopsy, which should be regarded as thegold standard for diagnosis. A biopsy procedure is indi-cated in any patient with a history suggestive of celiacsprue. This includes individuals with mild symptoms,particularly if they are relatives of probands. All patientswith DH require biopsy, not only to confirm the pres-ence of concomitant gluten-sensitive enteropathy, butalso to determine the severity of the enteropathy. How-ever, in the United States not all physicians performsmall intestinal biopsies in patients with DH. The mostcommon indications for performing a biopsy in child-hood are diarrhea, failure to thrive, anemia, and shortstature.

It is customary to take biopsies endoscopically. He-moglobin concentration, platelet count, and prothrom-bin time should be checked before biopsy because of thesignificant number of untreated celiac patients who havean increased prothrombin time. Anemia is not a contra-indication to small intestinal biopsy unless very markedbecause the risk of hemorrhage with a normal prothrom-bin time is small.

Endoscopic biopsy specimens should be obtained fromthe second part of the duodenum using the largest for-ceps available. It is advisable to take at least 3 biopsyspecimens to avoid difficulties in interpretation becauseof the normal villous mucosa overlying Brunner’sglands.32 The macroscopic appearance of the duodenumat endoscopy should be noted because a duodenal ulcer orpatchy duodenitis may produce a pattern of inflamma-tion similar to that found in celiac sprue. Sometimes theendoscopist may note either a loss or scalloping of thenormal duodenal folds (Figure 3).

Previously, small intestinal biopsy specimens weretaken with a suction-guillotine biopsy capsule, mostcommonly that of Crosby–Kugler or Watson. Certainpediatricians continue to use this biopsy technique toavoid the risk of general anesthesia in young children,although endoscopy with sedation for children may beused. The alternative capsule described by Bradburg,frequently termed a Quinton capsule or Ruben tube, maybe used to take multiple biopsy specimens of the smallintestine but is usually reserved for research purposes.

Serologic Markers

In untreated celiac sprue, there are raised sero-logic antibodies to gliadin, reticulin, jejunum, endomy-sium, and tTG (Table 2).32–36 It is important to remem-ber that these tests become negative when patients withceliac sprue take a gluten-free diet. Other food-relatedantibodies may also be raised in a nonspecific manner,which is thought to be a consequence of the increased


permeability of the small intestine in untreated celiacsprue.

Antireticulin antibodies. Antireticulin antibodieswere described in 1971 using immunofluorescence. It hasrecently been noted that they are specific but not verysensitive for celiac sprue, a finding confirmed in a recentstudy of 50 celiac children and 25 controls. Antireticulinantibodies are not commonly used having been super-ceded by antiendomysial and tTG antibody testing.

Antigliadin antibodies. Antibodies to wheat gli-adin, termed antigliadin antibodies (AGAs), have beenextensively studied in celiac sprue. In one study, thesensitivity of IgG AGAs and IgA AGAs were 100% and89%, respectively, in children with celiac sprue. Thespecificity was 86% for IgG and 95.5% for IgA AGAs.Subsequent investigators have confirmed that IgA AGAsare more specific for celiac sprue but less sensitive thanIgG AGAs. In the 2%–3% of individuals with celiacdisease, who are IgA deficient, all IgA antibody-basedtests will be negative. Therefore, screening for celiacdisease should include IgG AGAs, or IgG tTG antibod-ies or at least measurement of total serum IgA. ShouldIgA deficiency be found, it would be necessary to thenproceed to the IgG antibody tests. Care should be takenin the interpretation of positive results because AGAsmay also be raised in other conditions including cow’smilk intolerance and IgA nephropathy. Gliadin antibod-ies may be found in a variety of other conditions, namelyCrohn’s disease, eosinophilic enteritis, tropical sprue, andsome apparently normal individuals.

Antijejunum antibodies. Antibodies to the jeju-num have been identified, although they have not beenextensively studied in screening programs. It seems thatthey exhibit similar binding characteristics to antireti-culin and antiendomysial antibodies.

Antiendomysial antibodies. An antibody di-rected against endomysium, a connective tissue proteinfound between myofibrils in the gastrointestinal tract ofprimates, was found to be associated with gluten-sensi-tive enteropathy. Replacement of primate esophaguswith human umbilical cord as the substrate for antien-

domysial antibodies (EMAs) facilitated wider applicationof this test.30 The sensitivity and specificity of EMAsusing primate esophagus or human umbilical cord assubstrate are reported as 97%–100% and 98%–99%,respectively. EMAs seem to be superior to AGAs forscreening populations with a high prevalence of celiacsprue. The combination of AGAs and EMAs has positiveand negative predictive values approaching 100%. Thus,if either test is positive, the patient should be referred fordiagnostic small intestinal biopsy. However, if both testsare negative, it is highly unlikely that the individual hasceliac disease.

Another potential substrate for EMAs is cell culture–derived human umbilical vein endothelial cells. Whelan etal. has demonstrated 100% sensitivity and specificity foruntreated celiac sprue using such a method, although thefigures obtained by other investigators are somewhat lower.It has been suggested that the sensitivity of the assay mayfall to as low as 50% in certain commercial laboratories.

Anti-tTG antibodies. The demonstration that theantigen for EMA was tTG35 has allowed the develop-ment of an enzyme-linked immunosorbent assay for bothIgA and IgG tTG to screen for celiac sprue. Sulkanen etal.36 found that the IgA assay had a sensitivity of 95%and specificity of 94% in untreated celiac patients. Inaddition, all 14 of the IgA-deficient celiac patients weredetected using the IgG tTG enzyme-linked immunosor-bent assay. It should not be forgotten that the sensitivityof the serologic screening tests may be lower in certaincommercial laboratories.

Bone Metabolism

Osteomalacia is well recognized in celiac sprue,37

even in the absence of symptoms, and responds to cal-cium and vitamin D supplementation. Bone pain, pseudofractures, or deformity occur, but osteomalacia is fre-quently asymptomatic and only found after noting araised serum alkaline phosphatase level. Calcium andphosphate levels are frequently normal. Vitamin D(25(OH)D3) and parathyroid hormone levels are also

Table 2. Sensitivity and Specificity of Antibody Tests

Sensitivity Specificity Positive predictive Negative predictive

A B A B A B A B

IgA AEA 100 97 99 98 91 91? 100 98IgA ARA 91 68 99 100 91 100 99 77IgA AGA 91 52 85 94 45 87 99 74IgG AGA 76 88 88 92 46 88 97 92

Data from (A) Ferreira et al.32 and (B) Lerner et al.33

IgA AEA, antiendomysial antibodies; IgA ARA, antireticulin antibodies; IgA/IgG AGA, antigliadin antibodies.


useful. Bone biopsy gives absolute confirmation, al-though this is not frequently performed.

Osteopenia and osteoporosis are common features ofceliac sprue,38 although the exact mechanisms are un-clear. Bone mineral density is invariably reduced inuntreated celiac sprue but has also been found to bereduced in a high percentage of patients receiving agluten-free diet. One study involving dual energy x-rayabsorptiometry scanning, where osteoporosis was definedas a T score of less than 22SD, revealed that of 65patients on a gluten-free diet, 50% of women and 47%of men exhibited osteoporosis.38 Osteoporosis carries asignificant risk with increased morbidity, mortality, andsocioeconomic implications. Thus, screening of celiacsprue patients for osteoporosis by dual energy x-rayabsorptiometry is now recommended. Osteoporosis inchildren frequently responds to a gluten-free diet. Inadults, besides strict adherence to a gluten-free diet andconsideration of a repeat small intestinal biopsy, treat-ment may comprise hormone replacement therapy inpostmenopausal women, biphosphonates, or calcitonin.

In patients with osteopenia who are not actually os-teoporotic, repeat small intestinal biopsy proceduresshould be considered and the importance of strict adher-ence to a gluten–free diet emphasized. Dietary calciumsupplementation up to 1500 mg/day has been recom-mended, particularly for women at the menopause whowill suffer significant bone loss. Monitoring by repeatdual energy x-ray absorptiometry scan at 1 year should beconsidered because it permits an estimate of rate ofchange of bone mineral density.

Splenic Atrophy

This occurs commonly in celiac sprue, the mech-anisms being unknown. The finding of blood film fea-tures of hyposplenism, with Howell–Jolly bodies, with-out an obvious cause should prompt a search for celiacsprue. It has been suggested that pneumococcal immu-nization for those with hyposplenism should be consid-ered, although the value of this remains unproven.

Radiology

Dilatation of the colon was an early radiologicfeature to be noted. Segmentation and dilatation of thebowel and “moulage” resembling “a tube into which waxhad been poured and allowed to harden” were addedlater. After introduction of colloidal preparations of bar-ium, flocculation and segmentation were noted to occur.The most common feature remains dilatation. The upperlimit for the diameter of the normal proximal smallbowel on barium follow through is 30 mm in adults, 24mm in children aged 10 years, and 14 mm up to the age

of 6 months. The ileum does not show much distentionbut measures up to 24 mm in the normal adult. Valuesfor the technique of enteroclysis or small bowel enema inwhich barium is placed into the duodenum through aperoral or pernasal tube are higher. The upper limit forthe diameter of the small intestine in normal adultsusing this technique is 50 mm.

Barium follow through examination of the small in-testine reveals a loss of the fine, feathery mucosal patternwith thin mucosal folds in 85% of subjects (Figure 4).The normal appearance of the small bowel enema doesnot, however, include this feathery pattern. There isusually a degree of straightening of the valvulae con-niventes, thickening of the mucosal folds, and an increasein their separation. Superimposed upon dilatation andthickening of the mucosal folds are varying degrees offlocculation, segmentation, and clumping, which aremore relevant when they occur early in the examination.These features are not specific to celiac sprue.

Some patients have findings resembling Crohn’s dis-ease, but this usually involves strictures and ulceration.Other features resemble scleroderma, but this shouldreadily be differentiated on screening by the finding ofdecreased motility. A quarter of patients with untreatedceliac sprue do not have any radiologic abnormality.Radiologic examination, however, remains importantparticularly in the presence of abdominal pain to excludecomplicating lesions such as jejunal ulceration with stric-ture, lymphoma, or carcinoma.

TreatmentGluten-free Diet

Once a diagnosis of celiac sprue has been estab-lished, the conventional treatment is a gluten-free diet,which involves avoiding products containing wheat, rye,and barley. There is disagreement concerning the toxic-ity of oats; some physicians permit oats to be taken in thediet. Care should be exercised because the majority ofcommercially available oat flour is contaminated withwheat gluten. Dietary therapy should be initiated inconjunction with a dietician experienced in this area.There needs to be a careful explanation of the disease aswell as the provision of diet sheets. This is particularlyimportant in patients with few or absent symptoms. Theavoidance of future ill health and reversal of currentproblems, including anemia, osteoporosis, depression,and infertility, should be explained. Explaining increasedrisk of malignancy and in particular small intestinallymphoma is debatable and should be decided withdiscretion on a patient-by-patient basis. However, failureto disclose information about the patient’s illness that


may influence their perceived necessity for treatmentmay be hard to defend should later complications arise.Symptomatic improvement after the institution of agluten-free diet further confirms the diagnosis of celiacsprue.

It is helpful for patients to join a celiac support groupthat publishes lists of gluten-free products. There is nowa wide range of gluten-free breads, biscuits, pasta, etc. InEurope, these can frequently be obtained by prescription.Beer should be avoided because it contains considerablequantities of barley gluten prolamin (hordeins). Thephysician should be aware of foods that contain hiddensources of gluten, such as prepackaged breakfast cereals.These often contain malted barley, therefore smallamounts of gluten. The small amounts involved are nota problem for the majority, but may cause importantcombined symptoms in very sensitive celiacs. The mostcommon cause of relapse is gluten consumption, inad-vertent or otherwise. Physicians should not forget thatgluten may also be present in the excipient in certainmedications. It has recently been shown in a Finnishstudy that the majority of treated patients may ingestpure oats in the diet.39 Oats should not be included inthe diet because commercial oat flour is frequently con-taminated with wheat. However, if pure oat flour isavailable, this may be included in the diet. A gluten-freediet is low in roughage and therefore may induce trou-blesome constipation. This usually responds to the addi-tion of regular dietary rice bran and ispaghula husks.Specific dietary deficiencies that occur should be cor-rected. These include iron, folic acid, calcium, and, veryrarely, vitamin B12 deficiency.

After 3–4 months of therapy with a gluten-free diet,a repeat small intestinal biopsy specimen may be under-taken to show improvement in the appearance of thesmall intestinal mucosal biopsy morphology. If abnor-malities persist, other possible causes of small intestinalvillous atrophy such as giardiasis, or cow’s milk allergy,should be excluded. Even if symptomatic improvementhas occurred, the diet should be continued and a smallintestinal biopsy procedure may be repeated after a fur-ther 6–9 months.

An improvement in small intestinal biopsy morphol-ogy and symptoms normally occurs with a decrease inantibody titers to gliadin, reticulin, endomysium, andtTG. Should there be any doubt concerning the correctdiagnosis, further confirmation of the diagnosis by dem-onstration of deterioration of the small intestinal mor-phology in a repeat small intestinal biopsy procedureafter a gluten challenge is recommended. This is partic-ularly important in children in whom conditions such as

infectious diarrhea and cow’s milk intolerance may pro-duce abnormalities in small intestinal morphology. Themost convenient way to give a gluten challenge is to askthe patient to ingest at least 10 g of gluten in the formof 4 slices of normal gluten bread per day for 4–6 weeks.Should this induce severe symptoms, then the date of thebiopsy procedure may be brought forward. The EuropeanSociety of Paediatric Gastroenterology and Nutrition(ESPGAN) has recently suggested that it is not manda-tory to proceed to a repeat small intestinal biopsy pro-cedure after a gluten challenge if a gluten-free diet hasproduced a good improvement in symptoms and in themorphology of a follow-up small intestinal biopsy spec-imen.40 Many clinicians do not practice gluten challenge.In general, patients will experience significant symptom-atic improvement within days or weeks of commencinga gluten-free diet.

Failure to Respond to a Gluten-free Diet

Patients who fail to adhere strictly to a gluten-freediet frequently continue with ill health and recurringsymptoms that can usually be traced to dietary lapses,either deliberate or accidental. Earlier literature reportedthat 70% of celiac patients on a gluten-free diet quicklyreturn to normal health with improvement in 2 weeks.The remaining 30% can be divided into 3 groups. Thefirst group experienced progressive deterioration, whichwas halted in some cases by corticosteroids, but in othercases progressed to death. Patients in the second groupwere found to have an associated pancreatic lesion, andthose in the third group were found not to adhere strictlyto the diet, but even when this was corrected, their minorabdominal symptoms and diarrhea persisted.41

Steroids and Celiac Sprue

Celiac sprue can be controlled with systemic ste-roids with rapid cessation of diarrhea, weight gain, andimprovement of fat absorption. However, within a fewdays of stopping treatment, there is usually deterioration.Steroids are indicated in the treatment of celiac crisisincluding severe diarrhea, dehydration, weight loss, aci-dosis, hypocalcemia, and hypoproteinemia. They are alsoused to treat gliadin shock, an anaphylactic reaction togluten challenge, which can rarely occur in treated pa-tients.

Long-term steroids are rarely required in celiac spruebut are given to complement a gluten-free diet in casesin which the serum albumin is markedly depressed.Here, steroids may also bring the associated protein-losing enteropathy under control. The use of 6-mercap-topurine or azathioprine as a steroid-sparing agent hasbeen reported.42 Although there is a theoretical potential


for the use of more specific immunotherapy in the formof cyclosporin A, experience has shown that this agentdoes not help (Ciclitira PJ, personal observation).

The dose of steroids varies. Should a patient requireintravenous fluid replacement because of vomiting, diar-rhea, or surgery, hydrocortisone should be given intra-venously, 100 mg 6 hourly. A patient who is eatingnormally but exhibits a crisis should be given 40–60 mgprednisolone daily. The usual dose used for celiac spruethat has not responded adequately to a gluten-free diet is7.5–20 mg per day. It should be possible within anumber of weeks to reduce the higher dose. Failure to beable to do so should alert to the possibility of eitherfailure to adhere to the diet or a complication such aslymphoma or ulcerative jejunitis.

Follow-up

Following the initial assessment, diagnosis, andinitiation of a gluten-free diet, the question arises of howclosely and frequently the follow-up should occur. It hasbeen suggested that the vast majority of patients remainwell with strict adherence to a gluten-free diet. It isadvised that yearly assessment be undertaken withweight, full blood count, folate, calcium, and alkalinephosphatase. Serologic assessment with antibodies to gli-adin, reticulin, endomysium, or tTG may be useful be-cause elevated titers imply continued gluten ingestion.Follow-up should be lifelong. This allows reinforcementof the continuing need for strict adherence to the gluten-free diet and the early detection of any problem.

A significant proportion of patients do experienceproblems, and conditions known to be associated withceliac sprue should be watched for. These particularlyinclude diabetes mellitus, hypothyroidism, perniciousanemia, and hypoadrenalism.

Treatment of Complications

Many patients with celiac sprue exhibit lactoseand sucrose intolerance at diagnosis. A small percentageof treated celiac patients continue to be troubled withdisaccharidase deficiency. These conditions may be diag-nosed by either a hydrogen breath test or enzyme assaysof a small intestinal biopsy or by the appropriate sugarpermeability study.43 Should concomitant disaccharidasedeficiency be diagnosed, then the appropriate disaccha-ride should also be excluded from the gluten-free diet.

There are a small number of celiac patients who haveconcomitant small intestinal bacterial overgrowth. Thismay be diagnosed by hydrogen breath test, bile acidbreath test, or by an abnormally high bacteriologic countin a small intestinal aspirate. Should small intestinalbacterial overgrowth be a persistent problem, patients

may be treated with antibiotics such as 250 mg oxytet-racycline 4 times a day, which may be rotated fortnightlywith another, such as cotrimoxazole, 1 tablet twice a day.A short 10-day course of 200 mg metronidazole 3 timesa day is frequently helpful if small bowel bacterial over-growth is a problem, although the agent should not becontinued long-term because of neurologic side effects.

Complicating Ulcerative Enteritis

This is a rare complication of celiac sprue. It ischaracterized by multiple chronic small bowel ulcers,which are frequently caused by complicating lympho-ma.40

There is usually unexplained deterioration in a patientwith celiac sprue, although in many cases the latter maynot have been diagnosed. There is chronic diarrhea,abdominal pain, and weight loss. Small bowel radio-graphs are frequently abnormal, and the most suggestiveappearance is a narrowing of the intestine with efface-ment of the mucosal pattern, termed the moulage sign.Duodenal or jejunal strictures may be seen. Enteroscopyis useful because it allows multiple biopsy specimens ofthe small intestine to be taken. Laparotomy with a fullthickness biopsy of the small intestine may be required.Biopsy specimens should be investigated for T-cell re-ceptor clonality using polymerase chain reaction ampli-fication since T-cell receptor clonality should be consid-ered to suggest evidence of a T-cell lymphoma.

Many patients will require surgery either for diagnosisor for management of complications such as stricture orperforation. When feasible, surgical excision of the worstaffected segment of small bowel is the most appropriatetherapy. Corticosteroids are useful in a limited number ofpatients. Should a lymphoma be diagnosed, then appro-priate chemotherapy should be instituted with the aid ofan oncologist.

Malignancy

The prevalence of carcinoma of the gastrointesti-nal tract in celiac sprue is more common than in controls,particularly small intestinal adenocarcinoma and esoph-ageal and pharyngeal squamous carcinoma (Table 3).6

The prevalence of lymphoma in celiac sprue is 6%–8%, the incidence falling on prolonged treatment with agluten-free diet. Most cases present during the sixthdecade. Presentation often involves a return of symptomsof diarrhea, associated with both weight loss and pain.Manifestations such as fever, lymphadenopathy, hepato-splenomegaly, or abdominal masses or ascites may helpthe diagnostic conundrum but imply more advanceddisease. Alternative presentations include acute perfora-tion, obstruction, or hemorrhage.


Enteroscopy is useful, but an exploratory laparotomymay be required. Histology of peripheral lymph nodes,the liver, or bone marrow may provide a diagnosis.Abdominal ultrasonography, computer-generated to-mography, or nuclear magnetic resonance screening maybe useful. Blood tests are unhelpful, although hypoalbu-minemia and a high erythrocyte sedimentation rate arediagnostic pointers but are nonspecific. Thus, laparotomywith resection of suspicious areas of intestine togetherwith lymph node and liver biopsy procedures are fre-quently indicated.

Psychological and NeurologicComplications of Celiac Disease

Some patients with untreated celiac sprue havepsychological disturbances and may exhibit frank psy-chotic disease in the form of schizophrenia. These symp-toms usually respond to a gluten-free diet. Patients withceliac sprue may rarely exhibit severe neurologic disease.This may take the form of encephalopathy, cerebellardysfunction, myelopathy, peripheral neuropathy, or acombination of these. Calcification of the cerebral cortexhas been described.

An overview of neurologic complications reveals amainly male predominance compared with a backgroundof a higher incidence of celiac sprue in women. Unsteadi-ness of gait is a universal feature of the cerebellar degen-eration. Cranial nerves palsies and myoclonus may also beseen. Two contrasting patterns of neuropathological ab-normalities predominate. These are dorsal spinal columndegeneration of a type not dissimilar to that encounteredin subacute combined degeneration and a diffuse cere-bellar degeneration mainly affecting the cortical Purkinjecell population but also involving the dentate nuclei.The role of circulating antineuronal antibodies, althoughpostulated as a mechanism, remains unclear.

In the majority of affected subjects, the neurologicdisease progresses inexorably despite treatment with es-sential dietary trace constituents. However, the spinaldisease may improve in subjects receiving vitamins A, B,

and E. Multivitamins and trace element supplementsshould always be tried. It has been suggested that re-sponse to vitamin E implies that the development ofneurologic changes in celiac sprue may be related todeficiency of this substance.

Disease Associations

Numerous diseases are associated with celiacsprue (Table 4). There is an association with a variety ofautoimmune disorders that are linked to a raised preva-lence of HLA-DR3 and DQ2.

The coexistence of diabetes and celiac sprue is wellrecognized. The prevalence of insulin-dependent diabetesmellitus is reported to be between 6% and 8%. There isa higher than expected incidence of chronic hepatitis,biliary cirrhosis, and sclerosing cholangitis in celiacsprue. Chronic fibrosing alveolitis and other interstitiallung diseases including idiopathic pulmonary hemo-siderosis have been reported in association with celiacsprue. Ten percent to 15% of patients with celiac sprueexhibit concomitant distal ulcerative colitis. Patientswith proctocolitis complicating celiac sprue report im-provement with a gluten-free diet. They may requiretherapy with oral salazopyrine or mesalazine or cortico-steroid enemas. There is also an increased prevalence ofmicroscopic and lymphocytic colitis in celiac sprue, thesignificance of which is not fully understood. The dem-onstration of an inflammatory infiltration of the rectalmucosa in response to local gluten challenge in celiacsprue implies that the origin of the proctocolitis issimilar to that of the small intestinal enteropathy.45,46

Future Directions

Work continues on full characterization of allepitopes within gluten from wheat and related cereals.Such research may allow the development of novel cerealswith the baking and nutritional qualities of wheat, rye,and barley, but which do not exacerbate celiac sprue.

Table 3. Malignancy Occurring With Increased Incidence inCeliac Sprue

Malignancy Overall relative risk

All cancers 2–3Enteropathy-associated

T-cell lymphomas30–40 (7%) (if no gluten-free diet, no

increase if gluten-free diet .5years)

Small intestinaladenocarcinoma

83

Mouth, pharynx,esophagus

23 (no/partial gluten-free diet)

Table 4. Diseases Associated With Celiac Sprue

Prevalence

Atropic dermatitis UDermatitis herpetiformis 2%–3%Down’s syndrome UEpilepsy—with or without cerebral calcification UIgA deficiency 2%–5%IgA mesangial nephropathy UInsulin-dependent diabetes mellitus 8%Primary biliary cirrhosis USarcoidosis USjogren’s syndrome UThyroid disease 6%–8%

U, unknown.


Such approaches also include the possible development ofimmunomodulation for the future management of thecondition.

Current work on the genetics of the condition shouldclarify our understanding of the inheritance and patho-genesis of the condition, including the role of tTG inpartial deamidation of gluten proteins.

PAUL J. CICLITIRAProfessor of GastroenterologyGastroenterology Unit (GKT)The Rayne InstituteSt. Thomas’ HospitalLondon, England

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Address requests for reprints to: Chair, Clinical Practice and PracticeEconomics Committee, AGA National Office, c/o Membership Depart-ment, 7910 Woodmont Avenue, 7th Floor, Bethesda, Maryland20814. Fax: (301) 654-5920.

This work was supported by the American Gastroenterological As-sociation.


Documents

AGA Technical Review on Celiac Sprue - UAlberta