What are the recommended blood tests to determine whether or not someone has celiac

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1 FAQ: Diagnsing Celiac Disease Mre detailed answers are available n Hw is celiac disease (CD) diagnsed? What are the recmmended bld tests t determine whether r nt smene has celiac disease (CD)? Hw accurate are the bld tests? Hw lng des it take fr the ttg bld test fr celiac disease t be nrmal? Is it imprtant t have repeat bld tests r bipsies t cnfirm that I have celiac disease? I think I have celiac disease (CD), but I had a negative bld test. Hw d I knw if I have it? My dctr tld me I have celiac disease (CD), but I feel fine. Shuld I start the gluten-free diet? Why are peple smetimes diagnsed s late in life? Culd a persn have had it fr years and nt knwn it? Hw ften shuld a patient r family member f a patient have a repeat bld test if his/her test was negative? If a child has a sibling and a parent wh have been diagnsed with celiac disease (CD) by bth bld test and bipsy, d yu recmmend that the child have genetic testing even thugh his bld test was negative? The child in questin has n bvius symptms. What is the meaning f HLA-DQ2 and HLA-DQ8? D peple with celiac disease (CD) have ne r bth f the genes, HLA-DQ2 and HLA-DQ8, passed dwn frm their parents? Hw d yu inherit these genes? Can a parent have gluten sensitivity and the sn r daughter have CD? What is a gluten challenge? D I need ne? Is there a stl test t determine whether r nt I have celiac disease (CD)? Are high esinphil levels cnnected t celiac disease (CD) and/r allergies (such as pllen, mld, mildew and dust mites) r asthma? What is the difference between being sensitive t gluten and having celiac disease (CD)? Des nn-celiac gluten sensitivity cause visible damage in an endscpy/bipsy? Is it pssible that nn-celiac gluten sensitivity (NCGS) is a precursr t celiac disease (CD)?

2 Shuldn t every citizen in the U.S. be tested fr celiac disease (CD)? Hw is celiac disease (CD) diagnsed? CD is diagnsed by a gastrenterlgist. A patient wh is suspected t have CD will first have a bld test t check fr the celiac antibdies, either EMA r ttg, as well as a ttal IgA cunt. These first tw tests will determine if there are specific antibdies in the bld that are nly fund in patients with CD (1). Smetimes DGP, a test similar t ttg, is used. Read belw fr details n these tests. Visit Bld Tests under Medical Management n If the bld test is psitive, the patient will have an endscpy and a bipsy f the small intestine perfrmed by a gastrenterlgist. During the prcedure, the dctr uses a flexible device with a camera (endscpe) t remve a small amunt f tissue frm the small intestine usually frm the first part f the small intestine called the dudenum (1). A dctr will lk at the tissue under a micrscpe t determine whether there is damage t the intestine that is characteristic f CD. A bipsy is the gld standard fr the diagnsis f CD and is a necessary part f diagnsis. Visit Endscpy under Medical Management n It is imprtant that all these tests be dne BEFORE starting a gluten-free diet (GFD) (1). If testing is dne AFTER a GFD is started, bld tests can nrmalize and the intestine may have had a chance t heal. In this case, yur dctr will be unable t accurately diagnse CD. Starting a GFD withut first cnfirming the diagnsis f CD using bld tests and endscpy with bipsy f the small intestine is NOT recmmended. Hwever, if yu have already initiated a GFD based n a presumed diagnsis f celiac disease then yu will be advised t get a gene test (HLA-DQ2/HLA-DQ8) test t rule-ut the pssibility f celiac disease. T rule IN the pssibility f celiac disease yu will need an endscpy with a bipsy after a gluten challenge [see belw: What is a gluten challenge? D I need ne?] Taking the gluten challenge can be trublesme t sme patients as this might cause a temprary wrsening f symptms(1). Hence it is best t first get a definitive diagnsis n a gluten cntaining diet with bld tests and bipsy befre yu start a GFD. There is a secnd reasn fr nt starting the GFD befre a prper diagnsis. CD is a lifelng illness, nt nly requiring a life-lng GFD, but als invlving multiple parts f the bdy. It is pssible that ther illnesses respnsible fr symptms may be missed if yu are diagnsed incrrectly with CD based n reslutin f symptms alne. An imprtant diagnsis may be missed and/r yu may be fllwing a difficult diet that is nt imprving yur health. Depending n the patient's particular symptms and medical histry, a number f physical examinatins and lab studies may be carried ut t help identify nutritinal deficiencies, electrlyte abnrmalities r ther health cncerns. Physical Exam findings culd include:

3 Examinatin f the abdmen may reveal a blated stmach due t swelling f intestinal lps with fluids and gas Signs f weight lss such as muscle atrphy (lss f muscle mass) r lse skin flds Orthstatic hyptensin (a decrease in bld pressure when ging frm a seated r lying psitin t standing) Peripheral edema (a cllectin f fluids in the arms and legs) Bruising Dermatitis Herpetifrmis (DH) (see sectin n DH) Cheilsis (severely reddened and cracked lips; mst cmmnly seen at the crners f the muth) Glssitis (inflammatin f the tngue with frmatin f ulcers in the muth) Peripheral neurpathy (decreased sensatin r numbness in the fingers and tes) Physical exam findings related t hypcalcemia Chvstek's sign: tapping n a specific area f the face results in twitching f the facial muscle Trusseau's sign: inflatin f a bld pressure cuff n either arm results in a "carpal spasm," seen as flexing f the wrist Bld tests: Lw irn levels are cmmn (1). Ferritin is generally the best test t measure irn stres. Irn B12 and flate: Anemia due t deficiency in irn, flate and, in rare cases, vitamin B12 may be present(1). Vitamin D (25-OHD) (1) Zinc (1) Other tests that clinicians may rder depending n yur cnditin include: Parathyrid hrmne TSH (thyrid stimulating hrmne)

4 Ptassium Serum calcium Magnesium Fat sluble vitamins (with diarrhea) Carnitine Albumin (prtein stres) if malnutritin is suspected Chlesterl panel Stl examinatin: Lking fr bulky, greasy appearance and ful-smelling stls that can suggest imprper absrptin f fat Tests that actually measure the amunt f fat in the stl can als help t determine if this cnditin is present. Immunlgic testing/serlgy: Measurement f antibdy levels t: Tissue Transglutaminase (IgA-tTG) Endmysium (EMA) Gliadin deamidated gliadin peptide (DGP) Imaging studies: Imaging studies including x-rays, CT scans, and a variety f ther tests are rarely necessary in the diagnsis f celiac disease. Hwever, they may be needed t rule ut ther disrders in cases where the diagnsis is uncertain r t assess fr cmplicatins f celiac disease. X-rays f the small bwel can be taken after the patient swallws a substance knwn as barium. On the X-ray, the dctr may bserve dilatatin f the small intestine r an absence f the nrmal pattern f the small intestine due t destructin f the villi. Similarly, abdminal ultrasund has als been used t suggest the diagnsis f celiac disease but at this time imaging studies are nt rutinely recmmended in the diagnsis and fllw up f celiac disease. Bne density studies (als referred t as a DEXA scan) shuld be perfrmed in thse recently diagnsed with celiac disease. DEXA scans are usually recmmended after 12 mnths f strictly fllwing a gluten-free diet.

5 Prcedures: In the initial wrkup f celiac disease, an endscpic bipsy f the small intestine is usually perfrmed. A small tube with a vide camera n the tip is placed dwn the thrat and int the stmach and small intestine while the patient is sedated. The gastrenterlgist takes samples f tissue frm the small intestine, which can then be lked at under the micrscpe fr evidence f celiac disease. Visit Endscpy under Medical Management n The tests and prcedures listed abve are nt t be taken as all-inclusive. Depending n the extent f disease, further testing r referral t ther specialists may be necessary. Nnetheless, these are sme f the cmmn tests and results yu might find carried ut in an individual suspected f having celiac disease. Finally, imprvement f symptms upn the remval f gluten frm the diet prvides further clinical evidence f celiac disease. What are the recmmended bld tests t determine whether r nt smene has celiac disease (CD)? IgA-tTG and ttal IgA (immunglbulin A): Currently, the mst frequently used test is IgA anti-ttg, r tissue transglutaminase. The ttg IgA test will be psitive (>19) in abut 98% f patients with CD that have been n a gluten cntaining diet. We call this number the test s sensitivity. The same test will cme back negative (<20) in abut 95% f healthy peple withut CD. We call this the test s specificity. Ttal IgA: Yur dctr may additinally check yur ttal IgA level t determine if yu have an IgA deficiency, which is a harmless cnditin that is present in 2-3% f patients with CD. If smene is IgA deficient, they may have a false negative result t their EMA r ttg tests. In this case, yur dctr can rder a DGP test. He/she culd als rder an IgG ttg (immunglbulin G-tTG) test instead, althugh this is slightly less accurate than IgA ttg. DGP: (deamidated gliadin peptide) There are ccasinal individuals whse IgA-tTG results may be misleading. In this case, we recmmend using a newer test, anti-dgp (IgG and IgA antibdies t deamidated gliadin peptide)(1). It is similarly accurate t IgA-tTG and is useful fr patients with IgA deficiency. EMA: Anther bld test that yur dctr may rder is an EMA, r endmysial antibdy test. This test is used less frequently than the IgA anti-ttg, but since it detects the same target antigen n a tissue sectin it can be just as accurate. AGA: Anti-gliadin antibdies, r AGA, were used in the past, but are typically nt rutinely checked nw because they are much less accurate than ttg r EMA.

6 Gene Testing: If yur dctr is still uncertain as t whether r nt yu have CD, s/he may rder an HLA- DQ2 r HLA-DQ8 bld test. This is a genetic test that will help her/him determine whether r nt yu have CD. Again, this can nly rule ut the disease but will nt definitively cnfirm the disease. Visit Bld Tests, Endscpy and Genetics under Medical Management n Hw accurate are the bld tests? These bld tests are very accurate, especially when the ttg and EMA levels are elevated, as in patients with celiac disease (CD). In a small number f cases, thugh, a patient with CD may have a negative bld test. Visit Bld Tests under Medical Management n Hw lng des it take fr the ttg bld test fr celiac disease t be nrmal? It depends n the test. One f the tests used mst ften, tissue transglutaminase (ttg), has a half-life f six mnths. In ther wrds, it shuld drp by a half-fld in six mnths. Hence, if yu started ff at a ttg level in the thusands, it might take several years t nrmalize. Hwever, mst ttg levels nrmalize within several mnths t ne year in adults n the gluten-free diet. Evidence suggests that after 6 12 mnths f adherence t a GFD, 80 % f patients will test negative by bldwrk and in abut 90 % f thse adhering t the GFD fr 5 years (1). Many times it is tricky t predict when the test shuld becme nrmal since sme ttg tests dn t reprt values beynd a certain value. Fr example, ne test reprts values up t 120 mg/dl after which all values whether, in the hundreds r thusands, are reprted in the same manner, i.e. >120. Is it imprtant t have repeat bld tests r bipsies t cnfirm that I have celiac disease? It is imprtant t be accurately diagnsed with bld tests and a bipsy befre ging n a gluten-free diet. After starting the diet, fllw-up tests are individualized based n age, symptms, and ther health prblems. Rutine fllw-up with a dietitian skilled in celiac disease and a gastrenterlgist is strngly recmmended (1). In mst cases, bld tests are perfrmed n a regular basis, while repeat bipsies are nt usually necessary. A dctr will determine which specific tests are needed. I think I have celiac disease (CD), but I had a negative bld test. Hw d I knw if I have it? If yu are n a gluten-cntaining diet, and had a negative bld test fr CD, yu can elect t have a bipsy taken. Apprximately up t 5-16% f patients with CD have a negative bld test (1). If yur bld tests and yur dudenal bipsy are bth negative n a gluten cntaining diet, yu can cnclude that yu d nt have CD. If any new symptms develp ver time, yu can always be rechecked. Visit Screening and Bld Tests under Medical Management n Sme patients withut CD may experience discmfrt after ingesting gluten. These patients may feel better n a gluten-reduced diet. This cnditin is called nn celiac gluten sensitivity and is nt the same as celiac disease. Visit Nn-Celiac Gluten Sensitivity n

7 My dctr tld me I have celiac disease (CD), but I feel fine. Shuld I start the gluten-free diet? There is n evidence that strngly supprts recmmending a gluten-free diet if yu had a psitive bld test fr CD and/r bipsy findings f celiac disease, but n symptms f the disease. Hwever, the answer remains cntrversial and the experts are undecided. If yu have n symptms but yu have psitive bldwrk with evidence f small intestine damage in additin t evidence f ther rgan invlvement r nutritinal deficiencies then yu have a cnditin called silent celiac disease and may benefit frm a GFD. Hwever if yur intestinal bipsies are nrmal and yu have n evidence f ther rgan invlvement r nutritinal deficiencies then yu have a cnditin called ptential celiac disease. This may be especially true in children with high risk relatives wh are frequently tested (2). If an individual has n symptms at all, sme dctrs will wait and watch. Yur dctr will check ther lab values, thugh, t determine whether CD has had ther effects n yur bdy. Yu shuld be aware f symptms f CD that d nt affect yur gastrintestinal system that yu may be experiencing. Visit FAQs Assciated Cnditins n Other dctrs are mre aggressive and will recmmend that their patients start a gluten-free diet, especially if they are cncerned abut a pssible cancer risk. Due t the lack f clear guidelines it is best t talk t a celiac disease dctr abut the prs and cns f treatment fr CD. Why are peple smetimes diagnsed s late in life? Culd a persn have had it fr years and nt knwn it? The typical age f celiac diagnsis amng adults is smetime in their frties. It is very cmmn fr peple t have had it fr a while befre being diagnsed. The average time frm nset f gastrintestinal symptms until diagnsis is 11 years. This lag time might be significantly higher in peple wh have celiac disease but d nt have symptms. Hw ften shuld a patient r family member f a patient have a repeat bld test if his/her test was negative? If yur dctr has a strng suspicin that yu have celiac disease (CD), even with a negative bld test s/he may perfrm an endscpy with bipsy, as up t 5-16 % f patients with CD may have a falsely negative bld test (1). If the bld test and bipsy are nrmal then yu d nt have CD and there is n need fr repeat testing unless yur symptms change. Fr an adult relative f a persn with CD, there is n need t repeat a bld test unless the relative starts t develp symptms f CD. Children, hwever, may need t be tested regularly, and shuld see a pediatric gastrenterlgist. Visit Screening, Bld Tests and Endscpy under Medical Management n If a child has a sibling and a parent wh have been diagnsed with celiac disease (CD) by bth bld test and bipsy, d yu recmmend that the child have genetic testing even thugh his bld test was negative? The child in questin has n bvius symptms. This is a chice parents need t make fr themselves and their children. Hwever, children f parents with CD r with siblings with CD shuld cnsider the genetic test. If negative, CD can essentially be ruled

8 ut fr life, while the standard bld tests culd turn psitive in the future and s require repeated testing. What is the meaning f HLA-DQ2 and HLA-DQ8? HLA-DQ2 and HLA-DQ8 are the names f tw genetic markers which are part f the immune system and are able t stick t the gluten prteins. Every persn with celiac disease (CD) has at least ne f these genetic markers. If yur dctr is unsure as t whether r nt yu have CD, s/he can perfrm a simple bld test t determine whether r nt yu have ne r bth f these genes. If yu d nt have ne f these tw genetic markers, yur dctr can rule ut CD. If yu DO have ne f these genetic markers, it is pssible that yu have r may develp CD. Yur dctr will need t perfrm mre tests. Yu d nt need t eat gluten in rder t have the gene testing. D peple with celiac disease (CD) have ne r bth f the genes, HLA-DQ2 and HLA-DQ8, passed dwn frm their parents? Hw d yu inherit these genes? Can a parent have gluten sensitivity and the sn r daughter have CD? The Human Leukcyte Antigen (HLA) genes are linked t many autimmune diseases such as CD. Everyne has a cpy frm the mther and a cpy frm the father. These cpies can cme in different versins called alleles. The HLA gene alleles that predispse t CD are called DQ2 and DQ8. One may have DQ2 r DQ8 in ne f the cpies r in bth. Peple wh have nly ne cpy f DQ2 r DQ8 have a risk f abut 3% f having CD, whereas peple wh have tw cpies f either have a risk arund 10%. HLA types are actually cmbinatins f genes s it is pssible t be DQ2 psitive even if neither f yur parents has this gene. Overall thugh, at least 50% f children f parents carrying DQ2 r DQ8 will als have ne f these. Almst all peple with CD have at least ne DQ2 r DQ8 cpy. This is why genetic testing is s useful t rule ut CD. Nevertheless, since 30-40% f the general ppulatin has at least ne cpy f DQ2 r DQ8, the gene test is nt a gd test t cnfirm CD (1). T date, it is nt clear whether nn-celiac gluten sensitivity is assciated with the same genes linked t CD r any ther genes. While it is nt uncmmn t see families with different members being either celiac r nn-celiac gluten sensitive, we d nt knw at this pint whether this is caused by chance r nt. What is a gluten challenge? D I need ne? A gluten challenge is recmmended when a persn is n a gluten-free diet, but his/her dctr is unsure f whether r nt the patient has celiac disease (CD). Genetic testing can reslve this questin if celiac genes (HLA DQ2 and DQ8) are absent. If celiac genes are present a gluten challenge may be needed (1). In this case, gluten is reintrduced int the diet starting with ¼ slice f gluten cntaining bread and increasing t 2 slices f bread fr, ideally, 6-8 weeks (if the challenge can be tlerated fr that lng). Bld tests and an intestinal bipsy are perfrmed. If the gluten challenge is nt tlerable fr the full 8- week perid bld tests and bipsy can be perfrmed sner (3). Peple with cnfirmed CD d nt need t have a gluten challenge.

9 Nte that patients shuld ONLY underg a gluten challenge if instructed t d s by their dctr. Patients wh have been fllwing a gluten-free diet shuld nt reintrduce gluten int their diet withut talking t their dctr. Is there a stl test t determine whether r nt I have celiac disease (CD)? Stl tests have nt been prven t be effective in screening fr CD. Bld tests remain the mst effective and reliable way f screening fr CD. Hw des having a prblem with candida affect celiac disease (CD)? Candida albicans is a yeast that is part f ur nrmal digestive and skin flra. In certain cases when the immune system r the nrmal flra is altered (such as antibitic use, malnutritin, diabetes, etc.,), this usually harmless yeast can cause inflammatin f the skin as well as digestive and genital mucus surfaces. It may even get int the bldstream. Althugh there is sme crss reactivity that has been evidenced between gluten peptide and prteins n candida, actual causatin is difficult t establish at this time(4). Hence this thery is nt widely accepted. Are high esinphil levels cnnected t celiac disease (CD) and/r allergies (such as pllen, mld, mildew and dust mites) r asthma? Asthma, allergic rhinitis (hay fever) and atpic dermatitis are all part f a cmmn spectrum f diseases called atpic diseases. A cmmn finding in the bld wrk f peple with this spectrum f diseases is a high esinphil cunt. Sme researchers have fund that asthma and CD tend t happen tgether ften. Nevertheless, based n ur current knwledge, CD and atpic diseases are separate diseases with different bilgic mechanisms. What is the difference between being sensitive t gluten and having celiac disease (CD)? In nn-celiac gluten sensitivity (NCGS), a persn has gastrintestinal symptms frm gluten expsure but des nt have significant rise in ttg level (the bld test fr CD) r any damage t the small intestine. NCGS is nt believed t be triggered by a T-cell mediated immune respnse t gluten, as is the case with CD. In CD, gluten activates ne s immune system t attack the cells f the small intestine and cause damage. That is why ttg r ther celiac-specific markers rise. Often, it is nt easy t distinguish between these tw entities based n the clinical picture alne. Genetic testing, bld wrk and endscpy might be needed. Hwever, ur grup at BIDMC recently fund that peple wh reprt symptms with gluten expsure and wh have negative bld markers, n family histry f CD, n persnal histry f autimmune diseases (such as type I diabetes), and n diarrhea assciated with weight lss are extremely unlikely t have CD and d nt need endscpy(4). Visit Nn-Celiac Gluten Sensitivity n Des nn-celiac gluten sensitivity cause visible damage in an endscpy/bipsy?

10 Nn-celiac gluten sensitivity (NCGS) des nt cause visible damage f the small intestine in endscpy. But ccasinally, the bipsy may shw sme inflammatry cells nly. The presence f nrmal villus architecture is the characteristic feature f NCGS, unlike in celiac disease. Is it pssible that nn-celiac gluten sensitivity (NCGS) is a precursr t celiac disease (CD)? Current knwledge abut NCGS is still very limited. S far, mst research has failed t prve a cmmn bilgy in bth cnditins. Peple with NCGS ften have symptms that may be mre similar t Irritable Bwel Syndrme (IBS) than with CD but there is cnsiderable verlap in symptms. Sme research has shwn that patients with diarrhea-predminant Irritable Bwel Syndrme (IBS-D) may have gluten sensitivity. Als, accrding t guidelines, all patients with IBS-D shuld get screened fr CD. The true relatinship between CD, NCGS and IBS remains unknwn. At this pint, we believe that the risk f NCGS prgressing t CD is very lw. We await further studies f this issue. Shuldn t every citizen in the U.S. be tested fr celiac disease (CD)? Screening every persn in the US fr CD might nt be cst-effective given that it is estimated t affect nly abut 1% f the general ppulatin(1). Nnetheless, mst f the subjects wh have CD are nt aware f their diagnsis. This is due t insufficient screening in high risk individuals and lw disease awareness in the cmmunity. T imprve diagnsis rates, we recmmend screening adults and secnd degree relatives f peple with CD as well as peple with autimmune diseases wh have suggestive symptms. It is als recmmended that children f individuals with CD get screened nce even if they are nt symptmatic. Revisin Date: Authrs: Clinicians f the Celiac Center, Javier Villafuerte MD, with assistance frm Annie Peer Editrs: Melinda Dennis, MS, RD, LDN, Rupa Mukherjee MD, Satya Kurada MD, Daniel Leffler MD References 1. Rubi-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnsis and management f celiac disease. Am J Gastrenterl 2013;108:656-76; quiz Auricchi R, Tsc A, Piccl E, et al. Ptential celiac children: 9-year fllw-up n a glutencntaining diet. Am J Gastrenterl 2014;109: Leffler D, Schuppan D, Pallav K, et al. Kinetics f the histlgical, serlgical and symptmatic respnses t gluten challenge in adults with celiac disease. Gut 2013;62: Kabbani TA, Vanga RR, Leffler DA, et al. Celiac disease r nn-celiac gluten sensitivity? An apprach t clinical differential diagnsis. Am J Gastrenterl 2014;109:741-6; quiz 747.

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