celiac disease: ten things that every gastroenterologist should know

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Celiac Disease: Ten Things That Every Gastroenterologist Should Know Q7 Amy S. Oxentenko and Joseph A. Murray Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota There are Q4 10 things that all gastroenterologists should know about celiac disease. The immunoglobulin A tissue transglutaminase is the single best serologic test to use for the detection of celiac disease (CD). CD can be recognized endoscopically, and water immersion en- hances villi detection, although a normal endoscopic appearance does not preclude the diagnosis. It is rec- ommended that 4 biopsies be taken from the second part of the duodenum and 2 bulb biopsies be taken at the 9 oclock and 12 oclock positions to maximize the sensitivity for histologic conrmation of CD. Consider serologic testing of rst-degree relatives, patients with type 1 diabetes mellitus, Downs, Turners, and Wil- liamssyndromes, as well as those with premature osteoporosis, iron deciency, abnormal liver bio- chemistries, and other manifestations of CD. Patients already on a prolonged gluten-free diet (GFD) should be tested for the presence of HLA DQ2 or DQ8, thereby avoiding the need for further evaluation of CD in non- allelic carriers. The basic treatment of CD is a strict, lifelong GFD, enabled by an expert dietitian. Newly diagnosed adults with CD should be assessed for micronutrient deciencies (iron, B 12 , folate, zinc, cop- per), fat soluble vitamin deciencies (vitamin D), and bone densitometry. All patients diagnosed with CD should have clinical follow-up to ensure response and adherence to a GFD. In those with persistent or re- lapsing symptoms, the robustness of the original diag- nosis should be reviewed, gluten exposure sought, and a systematic evaluation for alternative and associated diseases performed. Evaluate those with refractory disease for malignant transformation. Keywords: --- Q5 . C eliac disease (CD) is increasingly common and topical for both the general and medical com- munities; therefore, gastroenterologists will be called on for expertise in this area. How CD is diagnosed has changed over time, and confusion abounds regarding the use and interpretation of diagnostic tests, which are often confounded by adoption of the gluten-free diet (GFD). Herein, we address 10 important things that gastroenterologists need to know about CD, which are based on current evidence and our experience in Mayo Clinics Celiac Disease Clinic. 1. How to Use Serology to Diagnose Celiac Disease Serologic testing for CD has signicantly advanced during the past 2 decades. The long-used anti-gliadin antibodies have been supplanted by serology with better test characteristics. 1 For example, endomysial antibody (EMA), used for more than 20 years, has specicity of 99%, 2 although the sensitivity varies because of the technical issues inherent in direct immunouorescence. This high specicity keeps EMA in use despite tissue transglutaminase (TTG) being identied as the targeted epitope. EMA is used primarily when discordance exists between other markers and histologic ndings 1 or when TTG immunoglobulin (Ig) A antibodies are equivocal. TTG antibodies come in both IgA-based and IgG- based assays, which are performed with enzyme-linked immunosorbent assay by using human recombinant/ derived proteins. IgA TTG has high sensitivity and specicity of w98% and is the endorsed serologic marker for evaluating CD. 3 It is well-known that IgA deciency affects 2%3% of CD patients and occurs in 1:131 patients tested for CD 4 ; thus, IgA-based assays alone are not always reliable. To avoid missing IgA- decient CD, a serologic cascade testing starting with serum IgA level can be performed, and if normal, an IgA TTG is adequate; however, if the IgA level is low or ab- sent, IgG-based testing with deamidated gliadin peptide (DGP) and/or TTG could be added/substituted 5 (Figure 1). The accuracy of IgG TTG is poor (30%70%) in IgA sufciency, so this test in isolation should not be used for routine CD screening. 6 However, IgG TTG performs well with known IgA deciency, with sensi- tivity and specicity approaching 95%. 2 Point-of-care nger stick TTG antibody testing has been developed as a rapid screen for CD, and although Abbreviations used in this paper: CD, celiac disease; DBE, double-balloon endoscopy; DGP, deamidated gliadin peptide; EATL, enteropathy-asso- ciated T-cell lymphoma; EMA, endomysial antibody; GFD, gluten-free diet; IDA, iron deciency anemia; Ig, immunoglobulin; MMA, methylmalonic acid; NRCD, nonresponsive celiac disease; RCD, refractory celiac dis- ease; TTG, tissue transglutaminase; T1DM, type 1 diabetes mellitus; VCE, video capsule endoscopy. © 2014 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2014.07.024 Clinical Gastroenterology and Hepatology 2014;-:-- FLA 5.2.0 DTD ĸ YJCGH53905_proof ĸ 11 August 2014 ĸ 5:16 pm ĸ ce CLR 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as corrected proofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

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Page 1: Celiac Disease: Ten Things That Every Gastroenterologist Should Know

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Clinical Gastroenterology and Hepatology 2014;-:-–-

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All studies published in Clinical Gastroenterology and Hepatology are embargoed until 3PM ET of the day they are published as correctedproofs on-line. Studies cannot be publicized as accepted manuscripts or uncorrected proofs.

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Celiac Disease: Ten Things That Every GastroenterologistShould Know

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Amy S. Oxentenko and Joseph A. Murray

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota

Abbreviations used in this paper: CD, celiac disease; DBE, double-balloonendoscopy; DGP, deamidated gliadin peptide; EATL, enteropathy-asso-ciated T-cell lymphoma; EMA, endomysial antibody; GFD, gluten-free diet;IDA, iron deficiency anemia; Ig, immunoglobulin; MMA, methylmalonicacid; NRCD, nonresponsive celiac disease; RCD, refractory celiac dis-ease; TTG, tissue transglutaminase; T1DM, type 1 diabetes mellitus; VCE,video capsule endoscopy.

© 2014 by the AGA Institute1542-3565/$36.00

http://dx.doi.org/10.1016/j.cgh.2014.07.024

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There are 10 things that all gastroenterologists shouldknow about celiac disease. The immunoglobulin A tissuetransglutaminase is the single best serologic test to usefor the detection of celiac disease (CD). CD can berecognized endoscopically, and water immersion en-hances villi detection, although a normal endoscopicappearance does not preclude the diagnosis. It is rec-ommended that 4 biopsies be taken from the secondpart of the duodenum and 2 bulb biopsies be taken atthe 9 o’clock and 12 o’clock positions to maximize thesensitivity for histologic confirmation of CD. Considerserologic testing of first-degree relatives, patients withtype 1 diabetes mellitus, Down’s, Turner’s, and Wil-liams’ syndromes, as well as those with prematureosteoporosis, iron deficiency, abnormal liver bio-chemistries, and other manifestations of CD. Patientsalready on a prolonged gluten-free diet (GFD) should betested for the presence of HLA DQ2 or DQ8, therebyavoiding the need for further evaluation of CD in non-allelic carriers. The basic treatment of CD is a strict,lifelong GFD, enabled by an expert dietitian. Newlydiagnosed adults with CD should be assessed formicronutrient deficiencies (iron, B12, folate, zinc, cop-per), fat soluble vitamin deficiencies (vitamin D), andbone densitometry. All patients diagnosed with CDshould have clinical follow-up to ensure response andadherence to a GFD. In those with persistent or re-lapsing symptoms, the robustness of the original diag-nosis should be reviewed, gluten exposure sought, and asystematic evaluation for alternative and associateddiseases performed. Evaluate those with refractorydisease for malignant transformation.

Keywords: ---.

Celiac disease (CD) is increasingly common andtopical for both the general and medical com-

munities; therefore, gastroenterologists will be calledon for expertise in this area. How CD is diagnosed haschanged over time, and confusion abounds regardingthe use and interpretation of diagnostic tests, whichare often confounded by adoption of the gluten-freediet (GFD). Herein, we address 10 important thingsthat gastroenterologists need to know about CD, whichare based on current evidence and our experience inMayo Clinic’s Celiac Disease Clinic.

FLA 5.2.0 DTD � YJCGH53905_proof �

1. How to Use Serology to DiagnoseCeliac Disease

Serologic testing for CD has significantly advancedduring the past 2 decades. The long-used anti-gliadinantibodies have been supplanted by serology with bettertest characteristics.1 For example, endomysial antibody(EMA), used for more than 20 years, has specificity of99%,2 although the sensitivity varies because of thetechnical issues inherent in direct immunofluorescence.This high specificity keeps EMA in use despite tissuetransglutaminase (TTG) being identified as the targetedepitope. EMA is used primarily when discordance existsbetween other markers and histologic findings1 or whenTTG immunoglobulin (Ig) A antibodies are equivocal.

TTG antibodies come in both IgA-based and IgG-based assays, which are performed with enzyme-linkedimmunosorbent assay by using human recombinant/derived proteins. IgA TTG has high sensitivity andspecificity of w98% and is the endorsed serologicmarker for evaluating CD.3 It is well-known that IgAdeficiency affects 2%–3% of CD patients and occurs in1:131 patients tested for CD4; thus, IgA-based assaysalone are not always reliable. To avoid missing IgA-deficient CD, a serologic cascade testing starting withserum IgA level can be performed, and if normal, an IgATTG is adequate; however, if the IgA level is low or ab-sent, IgG-based testing with deamidated gliadin peptide(DGP) and/or TTG could be added/substituted5

(Figure 1). The accuracy of IgG TTG is poor (30%–70%) in IgA sufficiency, so this test in isolation shouldnot be used for routine CD screening.6 However, IgG TTGperforms well with known IgA deficiency, with sensi-tivity and specificity approaching 95%.2

Point-of-care finger stick TTG antibody testing hasbeen developed as a rapid screen for CD, and although

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Figure 1. Schematicapproach to serologicdiagnosis of CD.

2 Oxentenko and Murray Clinical Gastroenterology and Hepatology Vol. -, No. -

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the specificity was reportedly 100%, the sensitivity wasonly 82%. It cannot be recommended until sensitivityimproves.7

The newest serologic marker is the DGP antibody,which comes in both IgA-based and IgG-based assays andis significantly better than anti-gliadin antibody testing.6

Despite specificity that is close to TTG assays, thesensitivity of either the IgA-based or IgG-based DGP inisolation is lower8; however, a combined IgA/IgG DGPpanel has accuracy equivalent to IgA-based TTG.2

In children older than 2 years, IgA TTG is thepreferred test. Serologic markers may have decreasedsensitivity in children younger than 2 years. The com-bination of DGP IgA/IgG with IgA TTG is the recom-mended strategy.3

Should panels of serologic studies for CD be morewidely used? The answer is no. The widespread use ofpanels would not be cost-effective as first-line testing;although it may slightly improve overall sensitivity, itreduces specificity, leading to unnecessary endoscopy.3

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Practical Suggestion

IgA-based TTG is the serologic test of choice for eval-uating CD in patients consuming a gluten-containing diet.

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IgG-based tests are needed in IgA deficiency. The use ofceliac cascade testing starting with serum IgA level coulddirect downstream serology. Equivocal or discrepantserologic tests should be interpreted with caution.

2. Can Celiac Disease Be RecognizedEndoscopically?

Gross Endoscopic Views

There are several well-described endoscopic featuresof CD, including mucosal fold loss, mosaic pattern, scal-loping, nodularity, fissuring, and prominent submucosalvascularity (Figure 2A and B). The sensitivity of endo-scopic markers varies (59%–94%), yet the specificity ishigh (92%–100%).9,10 The pattern of endoscopicmarkers may differ between adults and children. Amosaic pattern is found commonly in children, andalthough the frequency of other endoscopic markers ofCD increases with age, the mosaic pattern does not.

Water Immersion

Water immersion involves instilling 100–200 mLwater into the duodenum after deflation, takes only 30

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print&

web4C=FPO

Figure 2. Images of the duodenum in CD. (A) Typical changesof villous atrophy characterized by scalloping of the folds,mosaic pattern, and nodularity. (B) Loss of the folds in patientwith treated CD.

- 2014 --- Q13

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seconds to perform, has high sensitivity and specificityfor detecting total villous atrophy,11 and may help targetduodenal biopsies because of the patchy nature of CD.12

Combining water immersion with intravenous hyoscinebutylbromide may increase the positive predictive valueand specificity for CD compared with air insufflationalone (84% vs 99% and 87% vs 99%, respectively).13

Other Endoscopic Techniques

Video capsule endoscopy (VCE) may be indicated inpatients with CD who are unable to undergo upperendoscopy, have alarm features, or have normal histol-ogy but positive celiac serologies.14 VCE can examine theentire small bowel but lacks sensitivity for partial villousatrophy, is subject to interpretation, and lacks a stan-dardized grading system for CD. The sensitivity of VCE inCD is 89% with specificity of 95%.15

Although VCE adds little to the work-up of uncom-plicated CD, it is useful when evaluating refractory oratypical features.

Balloon-assisted endoscopy (DBE) or push entero-scopy may be useful in patients with CD who have patchysmall bowel involvement, disease limited to the jejunum,or in those undergoing an evaluation for complications ofthe disease. Antegrade DBE may uncover ulcerativejejunitis or enteropathy-associated T-cell lymphoma(EATL) and could be considered in CD patients with re-fractory celiac disease (RCD) type II, ongoing weight loss,continued intussusception despite a sustained GFD,suspicious lesions in the small intestine, or other alarmfeatures.

Chromoendoscopy enhances mucosal features of CDbut alone adds little to a skilled endoscopist. However,high-magnification endoscopy with chromoendoscopymay improve accuracy for detecting partial villous atro-phy compared with conventional endoscopy.16 Opticalband imaging may also enhance mucosal detail withoutdye to detect total and partial villous atrophy patterns.17

Practical Suggestion

Biopsy for CD is suggested, even in the absence ofendoscopic markers. Although novel techniques may

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enhance visualization of the mucosa, biopsies are stillneeded. Water immersion is simple and may be useful totarget biopsies or evaluate patients without a priorindication for biopsy.

3. What Biopsies Should Be Taken toEvaluate for Celiac Disease?

Endoscopically obtained, non-jumbo duodenal bi-opsies are standard for the evaluation of CD.18 Studiesreport that 10%–70% of non-oriented duodenal biopsieswere adequate for evaluation.19,20 Duodenal bulb bi-opsies increase the diagnostic yield for newly diagnosedCD by 9%–13% and uncover villous atrophy not seen onpost-bulbar biopsies in 14% with established CD.21,22

High sensitivity (100%) was achieved when 4 post-bulbar biopsies were combined with bulb biopsiesfrom both the 9 o’clock and 12 o’clock positions.3,23

Whether the post-bulbar and bulbar biopsies must besubmitted separately versus combined in 1 jar is unclear.

Practical Suggestion

Take 4 biopsies from the post-bulbar duodenum and1–2 biopsies from the 9 o’clock and/or 12 o’clock posi-tion of the bulb (Figure 3).

4. Which At-risk Patients Should BeTested for Celiac Disease?

First-degree relatives, especially siblings, of thosewith CD are at increased risk of CD.24–27 When siblingpairs have CD, the familial risk is further elevated.28 It iscontroversial whether asymptomatic family membersshould be tested. However, supposedly asymptomaticfamily members diagnosed with CD often uncover illhealth that improves on a GFD.29 Therefore, it isreasonable to consider testing all first-degree relatives.3

Providers should, at minimum, assess for clinical fea-tures of CD among relatives. In families with affected sibpairs, all first-degree and second-degree relatives shouldbe tested. Any family member with features of CD re-quires duodenal biopsies even if seronegative.30 HLAtesting is less helpful in family members because of thehigh likelihood of at-risk HLA alleles.31

CD is more common in type 1 diabetes mellitus(T1DM), with higher prevalence in children (3%–8%)compared with adults (2%–5%).30,32 Both conditionsshare the same HLA DQ2/8 alleles. Although some sug-gest that all patients with T1DM be screened for CD,33

most recommend testing only symptomatic pa-tients.30,34 However, patients with T1DM and features ofCD or repeated hypoglycemia should be evaluated. In anypatient with T1DM presenting for upper endoscopy,duodenal biopsies could be considered.30 Because of theshared HLA alleles between CD and T1DM, screening

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Figure 3.Optimal site for biopsy of CD, showing at least 4samples to be taken from second part of duodenum and 2samples from duodenal bulb, specifically at the 9 and 12o’clock positions.

4 Oxentenko and Murray Clinical Gastroenterology and Hepatology Vol. -, No. -

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should be done with serology. Duodenal biopsies shouldbe performed if there is high concern of CD despitenegative serologies. Screening for CD is not routinelyrecommended in those with thyroid and other autoim-mune conditions unless there are features of disease.30

Patients with Down’s syndrome are 5 times morelikely to develop CD compared with the general popu-lation,30 although prevalence rates vary.35 Althoughthere is not uniform consensus regarding screening forCD in those with Down’s syndrome,36 there is agreementthat patients with CD features be evaluated. Oneapproach in Down’s syndrome is to first testfor permissive haplotypes (HLA DQ2 and DQ8), andif absent, future testing is unnecessary.36 In thosewith permissive haplotypes, serologic surveillance is

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suggested. It is not known whether repeat future testingis needed. Patients with Turner’s and Williams’ syn-dromes are also at increased risk of CD.37,38

Practical Suggestion

Consider serologic testing for all first-degree relativesof a patient with CD, even those apparently asymptom-atic. Test relatives of affected sib pairs. Test symptomatic(and consider screening asymptomatic) patients withT1DM and Down’s, Turner’s, and Williams’ syndromes byusing serology in diabetic patients and HLA haplotypingin those with chromosomal abnormalities. In these pa-tients, diagnostic testing should be the terminology usedrather than screening to ensure insurance coverage.

5. How Does One Evaluate for CeliacDisease in a Patient on aGluten-free Diet?

With increasing frequency, patients start a GFDbefore testing for CD.39 With data showing that patientswith diarrhea-predominant irritable bowel syndromemay benefit from a GFD40,41 and because of the mediafocus on a GFD, the trend will continue. Although there islittle harm beyond cost to a patient on a balanced GFD,CD may be overlooked and complications ignored.

Ideally, patients who self-initiated a GFD should beevaluated for CD. First, determine the patient’s willing-ness to resume gluten intake for testing. In the patientwho refuses to resume eating gluten, this poses a chal-lenge. The sensitivity of serology and histology di-minishes with longer duration on a GFD.2 Althoughserology could be checked first,42 a positive result is theonly helpful result and indicates duodenal biopsies areneeded. However, if the patient has been on a GFD forless than 1 month, begin with serology because the yieldmay be reasonable in this period.3 In the patient on aprolonged GFD, HLA haplotyping can be done first.Although 30%–40% of the normal population will bepositive for HLA DQ2 or DQ8,43 the absence of permis-sive genes will allow 60%–70% of patients to be reas-sured that CD is ruled out. A gluten challenge should bediscussed for those carrying HLA DQ2 or DQ8 beforefurther testing.

In the past, a gluten challenge entailed consumptionof 8–10 g gluten daily for 4 weeks.30 However, as little as3 g gluten daily for 2 weeks will allow 75% of patients tomeet diagnostic criteria for CD.42 For those intolerant tothe gluten challenge after 2 weeks, serology andduodenal biopsies should be performed. In patientstolerating gluten ingestion after the 2-week period, thechallenge should continue 6 additional weeks, withserology performed after the 8-week challenge. Ifserology is positive, then duodenal biopsies are done. Ifseronegative, repeat serology after 2–6 additional weeksbecause a delayed rise in serologic titers may occur.42

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- 2014 --- 5

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Practical Suggestion

In patients requiring an evaluation for CD while on aGFD, testing for the presence of HLA DQ2 or DQ8 iden-tifies those requiring further testing. In patients positivefor HLA DQ2 or DQ8 and not highly sensitive to gluteningestion, testing after a low-dose (3 g daily) glutenchallenge for 6 weeks may suffice to diagnose CD.

6. How Is Celiac Disease Managed?

A strict, lifelong GFD, avoiding wheat, rye, and barley,remains the treatment of CD.3 How much is too much?Although the maximum safe amount of gluten for pa-tients with CD is unknown, <10 mg daily of gluten isprobably safe in preventing ongoing intestinal injury. Forfoods to be labeled as gluten-free, the Food and DrugAdministration requires there be <20 parts per millionof gluten in the product44; however, restaurants andfoods with meat, poultry, and eggs are not covered bythese regulations.

Previously, patients with CD were advised to avoidoats because of cross-contact or cross-sensitivity. Oatavoidance limits food choices.45 Oats belong to the samesubfamily as wheat, rye, and barley but to a differenttribe and contain very few deleterious peptides. Cross-sensitivity to oats may occur in highly sensitive pa-tients. Initial avoidance of oats should be considered innewly diagnosed CD with severe malabsorption, withreintroduction after 1 year when symptom-free.Although cross-contact of oats with gluten-containinggrains occurs, it is rare. For patients doing well on aGFD, pure oats can be consumed in moderation, but ifsymptoms recur or serologic titers rise, then withholdoats.3

All patients with CD should be referred to a dietitianwell-versed in a GFD. Guidelines are now available fordietitians to follow in regard to assessing patients withCD.46 If left to research a GFD on their own, patientsencounter misinformation47 and may unnecessarilyrestrict intake. Other practical topics addressed by di-etitians include how to avoid cross-contact at home (eg,separate toasters or jars of spread), travel and restauranttips, and reliable information on the Internet. In addition,it is necessary to review the overall health of a patient’sGFD, because obesity, diabetes, and other comorbiditiesare increasingly common.48

Patients with CD should have all medications andsupplements reviewed by a pharmacist to ensure thatthey are gluten-free,49 recognizing this may bemanufacturer-dependent. Food and Drug Administrationfood labeling rules do not apply to medications.

Practical Suggestion

All patients should follow a strict, lifelong GFDavoiding wheat, rye, and barley. All patients should be

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counseled on a GFD by an expert dietitian, and a phar-macist should review all medications and supplements.Oats should be eliminated for the first year in patientswith significant features of disease and only reintro-duced later if well-controlled.

7. What Should Be Assessed in thePatient With Newly DiagnosedCeliac Disease?

Vitamin and mineral deficiencies should be sought,and bone health should be assessed. Patients with overtmalabsorption may have multiple deficiencies of fatsoluble vitamins, minerals, and micronutrients.

Iron deficiency anemia (IDA) is a very commonmanifestation of CD, affecting up to 32% of adults; CD isfrequent in patients undergoing endoscopy for IDA.50 Acomplete blood count and ferritin should be assessed innewly diagnosed CD, and CD should be considered in allpatients with IDA without documented bleeding.

Vitamin B12 deficiency occurs in CD because of (1)terminal ileal involvement, (2) pancreatic insufficiency,or (3) concomitant autoimmune gastritis, which causesB12 deficiency in 10.5% of CD patients.51 Vitamin B12

deficiency occurs in 12%–41% of patients with CD,51 yetthe true prevalence may be higher because most studiesuse serum B12 levels without methylmalonic acid (MMA)levels. Because of the potential irreversible neurologicsequelae from untreated deficiency, all patients with CDshould have vitamin B12 levels checked, with follow-upMMA levels when B12 is low normal.

Folate is also absorbed in the proximal intestine, andalthough low levels of folate have been found in 35%–49% of CD patients, resultant anemia is less common.Serum folate levels may be normal to elevated in CD withconcomitant bacterial overgrowth. Folate levels shouldbe measured in CD, and emphasis should be placed onfolate supplementation in women of childbearing age.

Copper deficiency occurs in 6.8%–33% with CD52 andcan cause microcytic anemia, neutropenia, and throm-bocytopenia and rarely myeloneuropathy.53 Becausecopper deficiency may occur without anemia, levelsshould be checked in newly diagnosed patients to pre-vent neurologic sequelae. Zinc deficiency affects 20%–31% of patients with CD and can cause poor tissuehealing, dermatitis, or dysgeusia.52

Bone disease is frequent in CD, resulting frommalabsorption of calcium and/or vitamin D, with sub-sequent osteopenia, osteoporosis, or osteomalacia. Innewly diagnosed patients, the prevalence of osteoporosisis approximately 28% in the spine and 15% in the hip.Bone mineral density improves on a GFD, especially inthe first year54,55; however, fracture risk is increasedboth before and after diagnosis.56 Although vitamin Ddeficiency is common in CD, the prevalence of osteoma-lacia is unknown.54 All patients with CD should havecalcium and 25-hydroxyvitamin D levels at baseline, and

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many recommend bone densitometry for adults atdiagnosis3 or after 1 year to allow stabilization.54

Practical Suggestion

Patients with newly diagnosed CD should have acomplete blood count, ferritin, vitamin B12, folate, cop-per, zinc, calcium, and 25-hydroxy vitamin D checked.Parenteral vitamin B12 should be given with severedeficiency, neurologic features, or ongoing malabsorp-tion. Bone densitometry should be performed in adultswith CD.

8. How Are Adherence and Response toa Gluten-free Diet Measured?

Adherence to a GFD can be measured by self-report,dietitian inquiry, structured surveys, serologic titers,and assessment of mucosal healing. Most patients withCD will claim to be gluten-free; however, true adherenceranges from 42% to 91%.57 Multiple factors affectcompliance, including the ability to follow the GFD inrelation to changes (travel, dining out, social events,stress, mood), being involved in CD support groups, andcomprehension of the GFD. Although self-reporting maybe useful early in GFD, its reliability declines over time.

All CD patients should have a follow-up consultationwith a dietitian well-versed in the GFD if adherence isquestionable or additional resources are needed. Briefadherence surveys have been developed that are as good,if not better, than following serologic titers. The CeliacDietary Adherence Test is a 7-item validated question-naire that correlates with results of a structured dietitianassessment and serologic concentrations.58 Similarly, a1-minute, 4-question survey with a 5-level scoring sys-tem correlates well with serologic positivity, villous at-rophy, and celiac-related complications, with lowerscores predicting adverse outcomes.59

Once on a GFD, there is improvement of clinical,serologic, and histologic features, albeit at differing rates.In adults, diarrhea improves within days, with mean timeto symptom improvement of 4 weeks, and two-thirds ofpatients have complete resolution by 6 months.Abdominal pain, fecal incontinence, and bloating allimprove similarly.60 Failure of symptoms to improveshould prompt evaluation for associated disorders orceliac-related complications.61

Serologic titers fall soon after initiating a GFD, withsubstantially lower antibody levels at 1 year withongoing decline to negative/normal by 2 years. Althoughantibody levels will decline in incompletely compliantpatients, the rate of decline will be less than with strictcompliance.62 Normal serology does not guarantee strictGFD adherence; in addition, many patients have ongoingmucosal atrophy despite normal serology.63

Histologic improvement is slow in adults and delayedcompared with symptomatic or serologic improvement.64

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Mucosal recovery, defined by a villous:crypt ratio of 3:1,was present in 34% at 2 years and in 66% at 5 years,63

with healing complete in 90% by 9 years. Persistentinjury ismore likely in thosewho are noncompliant orwhohad severe symptoms or total villous atrophy atbaseline.63 Therefore, repeat biopsies after 1 year on aGFD may still show mucosal injury, and providers couldconsider waiting 2 years before assessing healing.Mucosal recovery is faster and more complete in children,with 95% recovery in 2 years and 100% recovery long-term in children following a GFD.

Physicians should provide consistency in the follow-up care of patients with CD.3 Currently, there is signifi-cant variability in the care provided,65 with suboptimalfollow-up of CD at 1 and 5 years of 41.0% and 88.7%,respectively.66

Practical Suggestion

A follow-up visit should be scheduled 3–6 monthsafter CD is diagnosed, with serologic titer consideredthen, and annual visits and serology thereafter. Assessfor adherence to a GFD with structured interview with anexpert dietitian. Patients can be assessed for histologicimprovement after 2 years on a GFD.

9. What Is the Approach to theNonresponsive Celiac Patient?

Nonresponsive celiac disease (NRCD) is defined as alack of response to 6 months on a GFD or recurrence ofceliac-related features despite compliance.30,67 NRCD iscommon and has been reported in 10%–19% withCD.68,69 Applying a stepwise approach to NRCD isimperative.3

The first step in those with NRCD is to verify thediagnosis of CD, reviewing baseline serologic titer(s) andintestinal biopsies. In the patient with enteropathy butnegative serology on a gluten-containing diet, othercauses of villous atrophy need to be considered,including, but not limited to, small intestinal bacterialovergrowth, autoimmune enteropathy, tropical sprue,drug-associated enteropathy (eg, olmesartan), Crohn’sdisease, combined variable immunodeficiency, collage-nous sprue, and eosinophilic gastroenteritis.70,71 CD canbe excluded by the absence of HLA DQ2 and DQ8.70

If the initial diagnosis of CD is robust, the next step isto evaluate whether gluten exposure (blatant, surrepti-tious, or inadvertent) is ongoing.61 A persistent orrecurrent elevation of serologic titer suggests gluteningestion, although a normal value does not ensurecompliance.72 There may be gluten exposure in non-fooditems such as medications, supplements, cosmetics, andglues.49,73

If gluten ingestion is unlikely, then duodenal biopsiesshould be performed. Biopsy the duodenum for RCD and

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the colon for microscopic colitis, which is 50-fold to72-fold more common in CD.74,75

If duodenal and colonic biopsies are normal, thenother causes of diarrhea need to be considered, such asdisaccharidase deficiency, small intestinal bacterialovergrowth, pancreatic insufficiency, or irritable bowelsyndrome; the latter is most common among theseassociated conditions and reported in 22% of NRCD.68

Practical Suggestion

In NRCD, verify the original CD diagnosis, and seekgluten ingestion. If gluten exposure is not present, thenduodenal and colonic biopsies can be helpful. If thesetests are negative, then systematic evaluation is needed.

10. What Do We Do With RefractoryCeliac Disease?

RCD is defined as recurrent or persistent villous atro-phy associated with malabsorption despite 12 months ormore on a verified GFD in patients with CD, without otherdiagnoses or gluten contamination.76 RCD affects only1.5% of CD patients.77 RCD is divided into 2 types. RCDtype I is defined as those who meet the definition of RCD,with polyclonal intraepithelial lymphocytes bearingtypical CD3 and CD8 surfacemarkers, whereas RCD type IIhas clonal T-cell receptors, without the typical CD3–T-cellreceptor surface markers, but preserved intracellular CD3expression.76 Of those with RCD, approximately 15% areRCD type II.77 Prognosis in RCD II is poor, with 5-yearsurvival at 44%–58%78–80 and a high risk of lymphoma.80

To evaluate for RCD, duodenal biopsies should undergoimmunophenotyping and T-cell rearrangement studies.RCD, ulcerative jejunitis, andEATL are complications of CDthat need to be considered carefully in NRCD.

Practical Suggestion

Ongoing villous atrophy should prompt immunophe-notyping and T-cell rearrangement studies to look forRCD II and lymphoma. RCD prompts further highlyspecialized investigations, including determination oftype and ongoing close surveillance for EATL.

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Reprint requestsAddress requests for reprints to: Joseph A. Murray, MD, Mayo Clinic, Divisionof Gastroenterology and Hepatology, 200 First Street SW, Rochester, Minne-sota 55905. e-mail: [email protected]; fax: (507) 255-6318.

Conflicts of interestThis author discloses the following: Joseph A. Murray received grant supportfrom Alba Therapeutics and Alvine Pharmaceuticals, Inc and is a consultant forEntera Health, Inc, AMAG Pharmaceuticals, Sonomaceutials, LLC, and Bio-LineRx. Amy S. Oxentenko discloses no conflicts.

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