autoimmune disorders and the role of non-celiac … · autoimmune disorders and the role of...

AUTOIMMUNE DISORDERS AND THE ROLE OF NON-CELIAC GLUTEN SENSITIVITY

TEN FACTS ABOUT

DR. THOMAS O’BRYAN, DC, CCN, DACBN

©2016 theDr.com | 877-GLUTEN1 (458-8361)

► Ten Facts about Autoimmune Disorders and the Role of Non-Celiac Gluten Sensitivity: by Dr. Tom O’Bryan. © 2016 theDr.com. www.theDr.com.

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Introduction Evenashortscanofthepublishedmedicalliteratureontheimpactofdiet,specificallyfoodallergiesandsensitivities,onthespectrumofautoimmunitycouldleadyoutoconcludethatdietarymodificationshavenoimpactoneithertheonsetoforarecoveryfromillness.

Forexample,researchersintheJournaloftheAmericanDieteticAssociationfoundnospecificnutrientdeficienciesinChronicFatigueSyndrome(CFS),alsoknownasMyalgicEncephalomyelitis(ME)andconcludeddietdidnotplayarole.DietaryguidelinesforCFS/MEremainasthoserecommendedbytheCenterForDiseaseControl(CDC)intheUSandabroad;CFSpatientsshouldsimplyfollowtheofficialgovernment“balanceddiet”guidelineswhichpromoteshighlevelsofstarchycarbohydrateslikegluten-containingbreadsandcereals.

Couldtheybemissingsomething?Iproposethattwodisordersassociatedwithsensitivitytotheglutenproductsingrains,CeliacDisease(CD)andNon-CeliacGlutenSensitivity(NCGS),arevastlyunderdiagnosedbothinthegeneralandCFSpopulation.Infact,studiessuggestundiagnosedGlutenSensitivitycontributestoearlymortality.

CeliacDisease–referstopeoplewithtotalvillousatrophyinthegutasaresultofimmunesensitivitytotheproteiningluten(gliadin),whichhasresultedinautoimmuneantibodiestothegutlining.

Non-CeliacGlutenSensitivity–includesbroadlytwocategoriesofpeople:

• First,thosewithonlypartialvillousatrophyorinflammationinthegut(whichthecurrenttestforCDmisses)inducedbysensitivitytogluten.

• Secondpeoplewithnogutimbalancesatall,butautoimmunitytootherorgansandsystems(e.g.thyroid)inducedbysensitivitytogluten.“CDisamuchgreaterproblemthanhaspreviouslybeenappreciated”ArchivesofInternalMedicineFebruary2003


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Autoimmunity and Celiac Disease Autoimmunedisordersarenowcumulativelythethirdleadingcauseofdeathintheindustrializedworld.Recognizedinabout24millionpeople,autoimmunedisordersarenowtheleadingcauseofdeathintheU.S.(andthoseareonlytheonesthathavebeendiagnosed).Whilemanyindividualautoimmunediseasesarerare,collectivelytheyarethoughttoaffectapproximately8percentoftheUnitedStatespopulation–24millionpersons.Toprovideacontexttoevaluatetheimpactofautoimmunediseases,canceraffectedapproximately9millionpeopleandheartdiseaseaffectedapproximately22millionpeopleintheUnitedStates.“Glutensensitivityisasystemicautoimmunediseasewithdiversemanifestations”LancetNeurologyMarch2010

Withdiagnosticratesatabout1outof3people,someformofautoimmunityisprobablypresentinatleast72millionpeopleintheUS.NIH.AutoimmuneDiseasesCoordinatingComm.AutoimmuneDiseasesResearchPlan2006

You are 10 times more likely to develop an autoimmune disorder if you have CD. Yes,youreadthatright.Asyouwillreadbelow,bothuntreatedCeliacandNCGSappeartosignificantlyincreasemortalityratesandCDisbeingimplicatedinalmostallautoimmunedisorders.

Morethan19,000papersonCDandthenewentityNCGShavebeenpublishedinPubMed.Despite(ormaybebecauseof)thevoluminousdata,noonehasworkedonconnectingthedotsandsynthesizingtheresultsinawaythatpatientsandbusypractitionerscanbothcomprehend.Thisiswheremyrolecomesinasaformerlybusyphysicianandfunctionalmedicinespecialist.

InmypreviouspracticeIspecializedinthetreatmentofCeliacandNCGS,beforeleavingitbehindtodedicateallofmytimeandenergytoeducatingotherdoctorsandpractitionersonthissubjectworldwide.

Youmightsay…Iamonamission.

InthiseBook,mygoalistosummarizekeyinformationfrompresentationsIhavesharedwiththemedicalcommunity,sothatboththeyandthegeneralpublicmayhavetheknowledgethatNCGSmaybeacontributingfactortoautoimmunedisease.

Icanalmostguaranteethatyourdoctor,gastroenterologistorevenyourspecialistdoesn’tknowmuchofthisinformationandprobablydoesn’tgraspitspotentialsignificanceinCFS/ME.

Dr.TomO’Bryan


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Surprised that Diet Could Play a Significant Role in Such a Serious Disease as Chronic Fatigue Syndrome? PatientsandpractitionersalikemaybesurprisedthatdietcanplayacriticalroleinseriouschroniccomplexillnessessuchasCFS/ME.Somemayevenfeelopposedtotheconceptthat“justdiet”andnotavirulentbugcouldbethecauseoramajorcontributortotheirCFS/ME.

Misconception and Misdiagnosis Misperceptionsregardingthenatureoffood‘allergy’thatstillpermeatemuchofthemedicalworldareattherootofthis.‘Classical’approachestounderstandingfoodallergiesassumereactionstofoodcanonlybeIgEmediated.IgEproducesclassicallergicreactionssuchas:sneezing,sniffling,rashesanddifficultybreathing.Weknowfromtheresearch,thatIgEfoodallergiesarelikelytoplayonlyasmallroleinCFS/MEpatients.

Celiacdisease(CD)andnon-celiacglutensensitivity(NCGS),however,areIgGandIgAmediatedimmuneresponsesthatcancausechronicgutinflammation,andverylikelychronicinflammatoryandautoimmuneprocesseselsewhereinthebody.

The Inflammatory Disease ‘Epidemic’ Inflammatorydisordershavebeenrapidlyincreasingoverthepastthirtyyears.ChronicinflammationandautoimmuneprocessesareimplicatedinALLofthemajorchroniccomplexillnessesthatblighthumanstoday.ThestudiescoveredinthiseBooksuggesta‘fireinthegut’i.e.,untreatedgutinflammationmayincreasetheriskofearlymortalityinallmajorchronicillnesses.

Foravarietyofreasonscoveredlater,includingtheintriguingevidencethatatleastasubgroupoftheCFS/MEpopulationhasanautoimmunedisorder,thefactsaboutCDandNCGSneedtobefullyunderstood.


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10 Facts Your Doctor or Gasteroenterologist Probably Doesn’t Know About Celiac Disease and Non Gluten Celiac Sensitivity (Ncgs) “foreverysymptomaticpatientwithceliacdiseasethereareeightpatientswithceliacdiseaseandnogastrointestinalsymptoms.”GastroenterologyFebruary2001

FACT 1:DuetoahistoricalmisconceptionthatCeliacDisease(CD)MUSTpresentwithgastrointestinal(GI)symptoms,CDisnottestedforinmanypatients,andthusisvastlyunderdiagnosed.

Thechancesare,ifyouhavefewornoGIsymptoms,yourDoctorwon’thavetestedyouforCD.NorisCDpartofthedifferentialdiagnosisforCFS/ME.Unfortunately,doctorsdon’trealizethatneurologicalsymptomsandawiderangeofothernon-GIsymptoms,mostofwhicharefoundinCFS/ME,shouldtriggerthetestforCD.

Thecurrentguidelinesforceliacdiseasesuggesttestingforitwherethereis”chronicfatigue,shortstature,delayedpuberty,dentalenameldefects,elevatedlivertransaminaselevels,dermatitisherpetiformis,andnutritionalanemias...”

Thebrainseemstobeparticularlyvulnerable…PediatricsAugust2001

CDwasoriginallybelievedtobefoundinpeoplewithdiarrhea,cramping,bloating,constipationandothergastrointestinalissues,stoolproblems,anemiaandweightloss.FurtherresearchrevealedCDanditsoffshootscommonlycausefatigue,weakness,osteoporosis,jointandbonepain,migraines,numbnessandtingling,depression,etc.

“Theicebergisacommonmodelusedtoexplaintheepidemiologyofcoeliacdisease.Themajorityofpatientshavewhatistermedsilentcoeliacdisease,whichmayremainundiagnosedbecausetheconditionhasno(GI)symptoms.”BritishMedicalJournalJuly1999


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Althoughceliacdiseasehasbeenknownforoverthirtyyearstocausebothgastrointestinalandneurologicalsymptoms,ittookuntil2000beforeceliacdiseasewasshown,insomeindividuals,tocauseonlyneurologicalsymptoms.Aslateas2010,areviewarticleinLancet,noless,notedthat‘onlyrecently’hasitbeenacceptedthatceliacdiseasecanpresentwithonlyneurologicalsymptoms.Infact,itappearsthatmostpeoplewithCDwhohaveneurologicalsymptomsdon’thavegastrointestinalsymptoms.


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FACT 2: ADiagnosisofceliacdiseasereferstotheENDSTAGEofthediseaseanddiagnosisofceliacdiseaserequiresTOTALVILLOUSATROPHY.CDtakesYEARStomanifestandisprecededbyGUTINFLAMMATION.TheseearlierstagesmaybedescribedaspartofNon-CeliacGlutenSensitivity(NCGS),butlikeceliacdiseasealso,stillmostlygoundiagnosedanduntreated.

IfyouhadanegativetestforCD,itmeansyoudidn’thavetotalvillousatrophy.Youcould,however,havepartialvillousatrophyorincreasedlymphocyteactivityinthegutliningwhichstandardtestingforCDmisses.

Thevilli,withtheirfinger-likeprojections,appearlikeshagcarpetsinthegut.Thevilli,withtheirhighsurfacearea,maximizenutrientabsorptionfromthegut.

Ifyouhavepartialvillousatrophyornovillousatrophyatall,yourCDtestwillbeNEGATIVE.

AlargeamountofinflammationinthegutcanstilloccurinpeoplenottestingpositiveforCD.Infact,it’sclearthattheprocessesthatresultintotalatrophyofthevillibeginmuch,muchearlierandareoftenevidentiftheyarelookedfor.Infact,someresearchersbelievethesearchfortherootsofceliacdiseaseshouldbeginearlyinlife,perhapseveninutero.

NormalvsAtrophiedVilli

Normallookingvilliontheleft;totalvillusatrophyontheright(requiredforcoeliacdiseasediagnosis)


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Totalvillousatrophydoesn’toccurovernight.Thegutinflammation(mucosalintraepitheliallymphocytosis)thatusuallyprecedesthewarzone-likestructuresoccurringintotalvillusatrophy,canbeidentified.Thelymphocytes,showninbrownbelow,areproducingthecytokinesthatwilleventuallydestroytheintestinalvilli,leadingto“totalvillousatrophy”or“CD.”

Studiessuggestthatthedegreeoflymphocyteinvasionpresentisamoreeffectiveandcertainlyearliertestforglutensensitivitythanchartingthedegreeofatrophyofthevilli.Inflammation(lymphocyteinvasion)comesfirst,followedbydamagetothevilli,followedbydestruction(atrophy)ofthevilli.Thepresenceofgluteninducedautoantibodiesisanotherearlytestwhich,ifthepersoncontinuestoconsumegluten,appearstobeabletopredicttheultimatedemiseoftheirvilli–(andtheirultimatediagnosiswithceliacdisease).IfweincludenownotonlyallCD,butalsoallthosewithNCGS,howmanypeoplesufferfromsomeformofglutensensitivity?312familymembers(FMs)ofCDdiseasepatientsweretestedforalltypesofglutensensitivityi.e.:CD,subclinicalandsilentforms.1outof5FMtestedpositive–suggesting20%ofthepopulationhavesomeformofglutensensitivity.“Wefoundahigh-prevalenceofCDbetweenCDFMs,andmostofthemwereolygo-orasymptomatic.”EuropeanreviewformedicalandpharmacologicalsciencesJune2010.


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FACT 3: UntreatedCeliacDisease(CD)andNonCeliacGlutenSensitivity(NCGS)IsAssociatedwithIncreasedMortalityRates.

YourmortalityrateisHIGHERwithNCGSandCDanddoesnotrequiretheend-stageoftotalvillousatrophy.“Theelevatedmortalityriskforallcausesofdeathcombined,reflectedforthemostpart,disorderscharacterizedbyimmunedysfunction”ArchivesofInternalMedicineJuly2003AlargeSwedishInpatientRegistrystudyinvestigatingmortalityrisksinmorethan10,000CDpatientsover30yearsfoundhavingCDincreasedtheriskofdeathfromaplethoraofmajordiseases.Thestudyexaminedstandardizedmortalityratio(SMR),whichchartstheincreasedlikelihoodofdeathifyouhavebothCDandanotherdisease.TheSMRof11.4,forinstance,innon-HodgkinsLymphoma(NHL),forinstance,indicatesapersonwithCDandNHLis11.4timesmorelikelytodieearlierfromNon-HodgkinslymphomathansomeonewiththatdiseaseandnoCD.Notethatmostofthesedisordersareassociatedwithimmunedysfunction.

• “Non-HodgkinsLymphoma(SMR11.4)• CancerofSI(SMR17.3)• InflammatoryBowelDiseases(SMR70.9)• AutoimmuneDiseases(includingRA)(SMR7.3)• DiffusediseaseofConnectiveTissue(SMR17.0)• AllergicDisorders(i.e.asthma)(SMR2.8)Diabetes(SMR3.0)• DisordersofImmuneDeficiency(SMR(20.9)Tuberculosis(SMR5.9)• Pneumonia(SMR2.9)• Nephritis(SMR5.4)”

Thelargesteverstudyofmortalityratesfoundceliacdiseaseinalmost10%of350,000plusbiopsiescollectedover40years,‘latent’CD(normalmucosabutpositivebloodwork)inabout1%(3.7K),andinflammationbutstillpartiallyintactvilliinabout5%(13K)ofthebiopsies.Resultsshowedincreasedmortalityratesinallthreecohortgroups;startlingly,mortalityrateswerehighestintheinflammation(Non-CeliacGlutenSensitive)group.•HRsinCoeliacdisease(HR,1.39;95%)(i.e.39%morelikelytodieearlier)•HRsinlatentCoeliacdisease(HR,1.35;95%)(35%morelikelytodieearlier)•HRsinpatientswithinflammation(HR,1.72;95%)(72%morelikelytodieearlier)


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When Ignorance is Not Bliss “IndividualswithCoeliacdiseasearetreatedwithagluten-freediet,whileveryfewwithinflammationare.Thosewithinflammationmayhaveanoverallworseprognosisthanthosewithvillousatrophy,sinceinstitutionofagluten-freedietoftenleadstonormalizationofthemucosa.”JournaloftheAmericanMedicalAssociationSept2009Whatcouldaccountforsuchalargeincreaseinmortalityinwhatappearedtobetheleastseverelyaffectedgroup?Properdiagnosis.Inthestudyauthorssuggestedthatpeoplewithceliacdiseasetendtogetdiagnosedandhealtheirgut.PeoplewithNCGS,however,oftendon’tgetdiagnosed.Intheircase,it’snottheceliacdiseasethatgetsthem,butthelong-terminflammatorystatethatincreasestheirriskofdyingfromanotherdisorder.Focus on Children “ChildrendiagnosedwithCoeliacdiseasehadathreefoldincreasedriskoflong-termmortality.ThisisinmarkedcontrasttotheexperienceofadultCoeliacdiseasewherethelong-termincreaseofmortalitywasmodest.Theincreasedmortalityinchildrenfromexternalcausesmayreflectbehaviouralchangeassociatedincopingwithachronicdiseaseanditstreatment.”AmericanJournalofGastroenterologyApril2007


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FACT 4: HavingCD/NCGSandnotadheringtoaglutenfreedietincreasesyourriskofdeath6fold.Theequivalentof1/90thofasliceofbreadcancauseseveresymptomsinthemostsensitive.CD/NCGSisPERMANENT.

“Deathwasmostsignificantlyaffectedbydiagnosticdelay,patternofpresentation,andadherencetotheGFD…Non-adherencetotheGFD,definedaseatingglutenonce-per-monthincreasedtherelativeriskofdeath6-fold…Ourresultsemphasizetheneedforpromptdiagnosisandtreatmentalsointhosepatientswithaminororsymptomlessformofcoeliacdisease.”Lancet2001ALancetstudyfollowingup1,072adultceliacsand3,384first-degreerelativesafter20yearsfoundtheSMRof2.0(200%)i.e.ifyouhaveCDyouaretwiceaslikelytodieearlythansomeonewithoutit.Remarkably,eatingevensmallamountsofgluten,placedceliacsatincreasedriskofdeath.Gluten Sensitivity is Permanent “CoeliacDiseaseisapermanentintolerancetoglutenthatresultsinimmunologicallymediatedinflammatorydamagetothesmallintestinemucosa”AmericanJournalofClinicalNutritionMarch1999Gluten-relateddisordersarepermanent;whileyourgutmayheal,yourglutensensitivityremainsandaddingglutenbackintoyourdietwillcausetheinflammationtorearupagain.Studieshavefoundthatevenafterfiveyearsonaglutenfreediet,thegutwilleventuallyflareupifyoureturntoeatingglutenproducts.Insomecases,evenverysmallamountsofglutencancausesystem-wideproblems.


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“Amilligramofglutenadaykeepsthemucosalrecoveryaway:acasereport”NutritionReviewinSept2004Afrustrated34yearoldwomanwenttoaCeliacspecialisttofindoutwhy,afterfollowingagluten-freedietforayearshewasstillnotbetter.Testingrevealedherantibodieswerestillskyhighandshehadtotalvillusatrophyandosteoporosis.Shewassufferingfromhairloss,poorskinandchronicfatigue,buthadagoodattitude.Thespecialistaskedhowstricthergluten-freedietwas.Afterbeingtoldshewasstilleatingtheoddamounteverymonth,shewastoldtocutoutglutencompletely.Ayearlaterherenergywasabitbetterandherantibodyresultswerehighnormalinsteadofsky-high,butherendoscopyresultswerestillbadandshestillhadhairlossandosteoporosis.ThespecialistagreedshewasindeedonaglutenfreedietbutthendiscoveredtheladywasaNun,andshewaseatingasmallpieceofhost(sacramentalbread)daily.Thespecialistmetthepriestandaskedforasampleofthehost.Thespecialistmeasureditandfoundthata30mgfragmentofwafercontainsapproximately0.5mgofgliadin(1mgofgluten).Thewomanrefusedtogiveupherdailysacramentuntilherpriestprevailedonhertodoso.Eighteenmonthslaterthewomancamebackradiantwithafullheadofhair,ahealthysmallintestineandnochronicfatigue.Thefragmentofthewaferwashalfathumbsize.


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FACT 5: AutoimmuneDisordersoccurtentimesmorecommonlyinpeoplewithceliacdisease(CD)thaninthenormalpopulation.CDtriggerstheproductionofautoimmuneantibodiesthatattackotherorgans.CDinitiatedautoimmunedisordersarelikelytobemisdiagnosed.(CDisalsocorrelatedwithmanynon-AutoimmuneDisorders.)

“Autoimmunediseasesarethethirdleadingcauseofmorbidityandmortalityintheindustrialisedworld,surpassedonlybycancerandheartdisease.”AnnalsoftherheumaticdiseasesSept2007Autoimmunedisordersarebelievedtoaffectapproximately8percentoftheUSpopulationor24millionpeople.That’smorepeoplethanareaffectedbyheartdisease(22million)orcancerofallforms(9million).ThissuggestsautoimmunedisordersmaybethenumberonecauseofdeathintheU.S.NIH.AutoimmuneDiseasesCoordinatingComm.AutoimmuneDiseasesResearchPlan.2006“Autoimmunedisordersoccur10timesmorecommonlyinCDthaninthegeneralpopulation.”TheautoimmunedisordersmostfrequentlyassociatedwithCDaretype1diabetesmellitusandautoimmunethyroiditis.ThepresenceofceliacdiseaseintypeIdiabetes,forinstance,isapproximatelytwenty-timeshigherthaninthegeneralpopulation.TheautoimmuneantibodiesassociatedwithCDincludeanti-endocrine,anti-gastrointestinal,anti-nuclear,anti-cytoskeletonandanti-neurologicalantibodies.CDisbelievedtotriggerautoimmunitythroughavarietyofmechanismsincludingHumanLeukocyteAntigen(HLA)andnon-HLAgenes,mimicry,alteredintestinalpermeability,epitopespreadingandothers.Onestudysuggestedlongdurationexposuretoglutenproductsisassociatedwithhigherratesofautoimmunityinceliacdisease.Thelongerceliacsareexposedtoglutenthegreatertherisktheyhaveofdevelopinganautoimmunedisorder.


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“OurdatashowforthefirsttimethattheprevalenceofautoimmunedisordersinCoeliacdiseaseisrelatedtothedurationofexposuretogluten”GastroenterologyAugust1999

TheagethepatientwasDiagnosedwithCD ThepresenceofotherautoimmuneconditioninadditiontoCD

2 5%

2-4 11%

4-12 17%

12-20 27%

>20 34%

Unfortunatelymostpeoplewithceliacdiseasespend5-10yearsgoingfromdoctortodoctorbeforeacorrectdiagnosisismade.“ThemajorityofCeliacpatientshadvisited5ormoredoctorspriortodiagnosis...andithadtakenanaverageof5to10years,afterinitialpresentation,forceliactobediagnosed.”KumarV,AmericanCeliacSociety,Nov.9,1996Other Disorders CDislinkedwithmanyotherdiseasesincludingliverandheartdiseases,osteoporosis,myopathies,schizophrenia,small-fibreneuropathyandmore:Celiacdiseasewasassociatedwithan8-foldincreasedriskofdeathfromlivercirrhosis.Aglutenfreediet,however,normalizesthelevelsofserumtransaminasesin75%to95%ofpatientswithCD.Infact,therateofceliacdiseaseinosteoporosisishighenoughthatsomerecommendallosteoporosispatientsundergoCDscreening.CDtriggeredinflammationappearstopossiblycauseorcontributetomyopathy,amuscledisordercharacterizedbymuscleweakness.Alargeepidemiologicalstudyinvolvingalmost80,000individualssuggestedthateverytypeofcardiovasculardiseaseisincreasedinpatientswithuntreatedceliacdisease.CDmayincreaseriskfactorsformentaldisorderssuchasschizophrenia.Oneresearchstudyproposesthatschizophreniaisrareincultureswithlowglutenconsumption.Anotherpopulationstudy,however,didnotfindalinkbetweenschizophreniaandCD.RatesofdepressioninCDandgastrointestinaldisordersdonotappeartobeincreasedrelativetohealthycontrols.


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Peripheral Neuropathy IgGantibodieswerepresentin34%andbiopsydemonstratedvillidestruction(celiacdisease)in9%ofpeoplewithidiopathicperipheralneuropathyincludingsmall-fiberneuropathy.(Anotherstudy,however,concludedthetwowerenotlinked.)However,alargeSwedishstudyinvolving14,000peoplewithceliacdiseaseand70,000healthycontrolsfoundincreasedriskofperipheralneuropathy(butnotincreasedrisksofneurologicaldisorderssuchasParkinson’s,Alzheimer’s,multiplesclerosis,Huntington’sdiseaseandmyastheniagravis).Inthestudy,authorssuggestedpeoplewithperipheralneuropathyshouldbetestedforCD.Recentstudiessuggestaformofperipheralneuropathycalledsmallfiberneuropathyiscommoninfibromyalgia.Glutensensitivitywaspresentinathirdofpatientswithsensoryganglionopathy(SG),adisordercharacterizedbydamagetothecranialandspinalganglia,usuallybyautoimmuneprocesses.Autopsiesofthethreeglutensensitive,SGpatientsindicateddamagetothedorsalganglia.Swedish Studies Swedenhasputitslargemedicaldatabasestogooduseinmanyceliacstudies.AdultceliacdiseasewasassociatedwithincreasedriskofpancreatitisinanotherSwedishstudy.AlargeSwedishstudyfoundceliacdiseasetobeassociatedwithincreasedriskofaraftofliverdiseasesincludinghepatitis,liverfailure,primarybiliarycirrhosis,livercirrhosisandfibrosisandfattyliver.Ratesofdepressionincreasedafterceliacdisease(butnotbeforeit).Immunedysfunctioninbothceliacdiseaseandsarcoidosiswasbelievedtoplayaroleinincreasedratesofsarcoidosisinpeoplewithceliacdisease.Immunedysfunctionandinflammationwasbelievedtobebehindincreasedratesofkidneydiseaseaswell.EvenfracturesgotintheactwiththeSwede’sfindingincreasedriskofhipandotherfracturesinpeoplewithCD.Increasedriskswerealsofoundindiabetes(relativelylowrisk),thyroiddiseaseandadrenaldisease(greatlyincreased).


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FACT 6: NCGSmaytriggerautoimmunityviagutinflammationorviamolecularmimicry-withnogutinvolvementatall.

…Whenthefinelytunedtraffickingofmacromoleculesisdysregulatedingeneticallysusceptibleindividuals,bothintestinalandextraintestinalautoimmunedisorderscanoccur…Natureclinicalpractice.Gastroenterology&hepatologySept2005

AlthoughresearchhasyettoconfirmthelinkbetweenautoimmunityandNCGS,thelargeststudyevercompletedonglutensensitivitysuggestsmortalityratesarehigherforpeoplewithnon-celiacglutendisorder(NCGS)thanCoeliacdisease(CD).Thatsuggestsit’sprobablyjustamatteroftimebeforesimilarcorrelationsregardingautoimmunityaremadeintheliterature.Indeed,thestudyfoundthatpeoplewithgutinflammation(whichischaracteristicofNCGS)arealsohighlylikelytosufferfrom“leakygut”whichisstronglyassociatedwiththeonsetofautoimmunedisorders.TheGItractregulatestheflowofmacromoleculesbetweenthegutandtherestofthebody.Someresearchersbelievetheintroductionofharmfulmacromoleculesintothebloodstreamcommonlytriggersautoimmuneprocessesboth,insideoroutsideofthegut.Itisalsoimportanttounderstandthatevenifyourgutexhibitsnovillousatrophy(celiacdisease),andnointraepitheliallymphocytosis(inflammation)inthegut,youcanstilltestpositiveforglutensensitivity(positiveIgAandIgGbloodteststogluten)andyourglutensensitivitymaybetriggeringincreasedautoimmuneantibodiestoawholerangeofdifferentorgansinthebody.Whichspecificantibodiesyoudevelopmaydependonyourindividualgeneticmake-upor“weak-link”inthechain.“Antigenicmimicry”isonemethod.It’sthoughtthatCDcausesautoimmunitytoorgansoutsidethegut.Asthebodybecomessensitizedtogluten,itcanstarttoattackarangeofmoleculesthataresimilartogluten,likethoseassociatedwiththethyroidgland.


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“Thecommonimmunogenetictheories….aresharingcommonHLAandnon-HLAgenes,antigenicmimicry,damage-inducedneoantigenexposure,alteredintestinalpermeability,idiotypenetworkdysregulationandepitopespreading.”AutoimmunityReviewsSept2007ThebelowautoantibodieshavebeenassociatedwithCD;noticethatmostdoinvolvethegut.

Accordingtothelatesttextbook:AdvancingMedicinewithFoodandNutrients2ndEdition,correlationsbetweentheillnessesbelowandNCGShavebeenconfirmedintheliterature:

• IgANephropathy• Epilepsy• Myalgia/Myositis• CerebellarAtaxia• PeripheralNeuropathy• Brainatrophy• Irritablebowelsyndrome• Schizophrenia


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FACT 7: WhereCD/NCGShasaffectedthegut,takingglutenoutofthedietisNOTenoughforclinicalimprovement.ThefireofinflammationinthegutmustbeputoutandintestinalpermeabilityMUSTbehealedtorestoreabsorption.Takingglutenoutstopsfeedingthefire,buttheinflammatorycascadehasalifeofitsownandgutpermeabilitycontinuesunlessthereisaspecifichealingintervention.

Lessthanhalfofpatientswithcoeliacdiseaseonagluten-freediethavecompletenormalizationofintestinalbiopsies,intestinalpermeabilitydefects,andantibodylevels(afterameanof9.7yearsonaGFD).DigestivediseasesandsciencesApril2010

ItisimportanttounderstandthatchildrenwithCDhada3foldincreaseoflong-termmortality–WHETHERTHEYWEREONAGLUTEN-FREEDIETORNOTaccordingtoAmericanJournalofGastroenterologyApril2007

Thissuggeststakingglutenoutofthedietisnotenough.AlthoughthevilliofCDpatientsgrowsbackafter1yearonagluten-freediet,theevidencesuggeststhatincreasedintestinalpermeabilityandpoorabsorption–bothlinkedwithautoimmunity–isstillpresent.Sothegutmustbehealedandanyinflammatorycascadedealtwithevenafterglutenisremoved.

“Thereisastrongactivationofimmuno-inflammation,bothinintestinalbiopsysamplesandinperipheralbloodcellsinpatientswithactiveCD,withahighchronicreleaseofvariouscytokinesandothermoleculeswithvasoactivepropertiessuchasinterferon-andinterleukins2,4,and10”TheAmericanJournalofGastroenterologyMarch2003

“Gliadinactivationofmacrophageswasfoundtoup-regulateexpressionofapanelofinflammatorygenesandresultinthesecretionofinflammatorycytokines.”TheJournalofImmunologyFeb2006

Thedifficultyofadheringtoagluten-freediet(GFD)canmakeprognosisdifficult.StrictadherencetoaGFDdoesgreatlyimprovenutritionalstatusbutonestudyfounditdidnotcompletelynormalize‘bodycomposition’.MetabolizingB-vitamins,inparticular,maybereduced.Hallertet.al.foundthatevenceliacpatientsonlong-termgluten-freedietswithnormalgutvilli,hadreducedplasmaB-vitamin(homocysteine)levels.Forty-fivepercentof


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celiacdiseasepatientsonaglutenfreedietfordecadeshadreducedbonemineraldensity(osteoporosis).Increasedratesofdiseaseindicatethatneurologicalproblemscanmanifestthemselvesevenwhen‘overtmalabsorption’isnotpresentinsomepatients.Whilesubstantialimprovementingutmucosaandotherfactorsdidoccur2-4yearsafterbeginningagluten-freediet,lactaseactivitywasstillreduced.Onestudysuggested‘leakygut’wasstillcommonayearafterbeginningagluten-freediet.Finally,qualityoflifemeasuresimproveafterinitiatingagluten-freedietbutarestillsomewhatreducedrelativetothegeneralpopulation,sosimplyremovinggluten,whilebeneficial,isoftennotsufficienttoreturnonetofullhealth.

The Cross-sensitization Factor: Taking gluten out of the diet may not be enough because of the issue of cross-sensitization. Evenminutetracesofgliadinortheircross-reactivefoodsarecapableoftriggeringastateofheightenedimmunologicalactivityinglutensensitivepeople.Journalofneurology,neurosurgery,andpsychiatry.Dec1997

Cross-sensitizationreferstoaprocesswhere-byapersonbecomessensitizedtonewsubstances.Forinstance,inglutensensitivity,theoriginalsensitivitytoproteinscalledgliadinsfoundincerealsintheTriticumgenus(wheat,ryeandbarley)canleadtofurthersensitizationtootherproduce.

Foodsknowntocrossreactwithpurifiedgliadins(wheatproteins)makeuptheentirefirstline(rye,barley,spelt,cow’smilk,wheyproteinplusmilkchocolateandcoffee).Theotherfoodsonthechartarecommonlyeatenonagluten-freedietwheresensitivitymayalsoarise.Somefoodssuchasoatsarepreparedinfacilitieswhereglutencontaminationiscommon.Evensmalltracesofgliadincantriggeranimmuneresponseinveryglutensensitivepeople.


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FACT 8: ThecurrenttestforCDnotonlymissesoutontestingforcross-sensitizedfoodsbutalsoignoresthefactthatpeoplereacttoaRANGEofglutenproteins,hencefalsenegativesareprevalentinthestandardCeliactest.Also,thereareatleast24celiac-associatedauto-antibodiesthatcouldbetestedfor,notjustgutrelatedautoantibodies

TheStandardcoeliactestismadeupofthreeelements:

TwoantibodiestopartsoftheBODY–ieAUTOIMMUNITYinthegut:

1/Totheendomysium–thesheathwhichenclosesthevilli

2/Totransglutaminase–anenzymeinsidetheendomysium

Antibodiestoanenvironmentalfactor–i.e.ALLERGYtogluten

3/Antibodiestotheglutenproteingliadin.RecentlythishaschangedtodeamidatedglutenwhichhasbeenfoundtobemoreaccuratetodiagnoseCD,butnotNCGS.

Problems With The Current Testing Protocols (1) AntibodiestoendomysiumandtransglutaminaseareEXECELLENTmarkersforTOTAL

VILLUSATROPHY(i.e.celiacdisease)butarehighlyunreliablediagnosticmarkersforthepartialvillousatrophyorincreasedepitheliallymphocytesfoundinnon-celiacglutensensitivity(NCGS).Only24%ofpatientswithpartialvillousatrophy(NCGS)andcoeliacdiseasewerediagnosedcorrectlyusingantibodytestsintwostudies.

TheantibodytesttotheglutenproteinONLYchecksforoneTYPEofgluten(calledthe33-merpeptide.)Ifallyoudoischeckthegluten33-mer(thestandardtest)you’llmissglutensensitivity50%ofthetime.StudiesconsistentlyshowthatmostpeoplewithCDreacttoarangeofglutenpeptides,someasstronglyasthegluten-33merthatistypicallytestedfor.NoteglutenisfoundinALLgrains,howeverasubsetofglutenproteinsparticularlytoxictosomehumansarefoundinwheat,ryeandsoon.AnassaythatincludesIgAandIgGantibodiesforarangeofglutenpeptidesisthereforedesirable.


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“OurpresentresultsindicatethatCDpatientsarecapableofrespondingtoalargearrayofglutenpeptides.Wefoundthat50%ofthesepatientsdonotrespondtothealpha-GLIApeptidebuttoadiversesetofgliadinandgluteninpeptides,including6novelepitopes.”GastroenterologyJune2002

Prevalence Ifwetakeintoaccountthatglutensensitivitydoesn’tjustcauseCD,butalsopartialvillousatrophyandgutinflammation,ANDprobablytriggersmanydisordersoutsidethegutincludingautoimmunedisorders,ANDthefactthatpeoplereacttoarangeofglutenmolecules,notjusttheoneinthestandardCD,itbegsthequestion;howmuchofthepopulationissensitivetosomeformofgluten?

Ibelieveitisbetween10%and35%ofthepopulation.

“GlutenSensitivity(GS)isastateofheightenedimmunologicalresponsivenesstoingestedgluteningeneticallysusceptiblepeople.Itrepresentsaspectrumofdiversemanifestations,ofwhich,theglutensensitiveenteropathyknownasCDisoneofmany.Adversereactionstothetoxicfamilyofglutenproteinsfoundinwheat,barley,rye,andtheirderivativesmaytriggeraheterogeneoussetofconditions,includingwheatallergy(IgE),NCGS,andCD,that,combined,affectbetween10–35%ofthepopulation.”CeliacDiseaseandNon-CeliacGlutenSensitivity:theEvolvingSpectrum


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FACT 9: ThelimitedresearchondietaryinterventionisstillmainlybasedontheclassicalapproachtofoodallergywhichisIgEmediated.Despiteclearevidencefornon-IgEmediatedfoodsensitivities,manystudiescontinuetoignoretheresearch

Forexample,theScandinavianJournalofGastroenterologyinSept2012inthepapercalled“Functionalbowelsymptoms,fibromyalgiaandfatigue:afood-inducedtriad?”researchersreported:

“Inaprospectivestudy,84patientsreferredtoouroutpatientclinicforinvestigationofperceivedfoodhypersensitivitywereenrolledconsecutively…

…NeitherIgE-mediatedfoodallergynororganicpathologycouldexplainthepatients'symptoms.”

TheabovepaperdidnottestforCD,orNCGSnorIgGorIgAcross-sensitisedfoodsandreflectswhatManuetalconcludedbackin1993below,whichisessentiallythatCFSpatients’assertionsthatself-reportedintolerancestofoodarementaloremotionalinorigin.

“Intolerancetovariousfoodsisreportedoftenbypatientsseekingevaluationforchronicfatigue…Toassesstheprevalenceandsignificanceofthisphenomenonwestudied200consecutivepatientswithchronicfatiguewhoweregivenacomprehensivemedicalandpsychiatricevaluation...

Thesedatasuggestthatintolerancetomultiplefoodsisprobablynotacauseortheeffectofchronicfatigue,butratheroneofthemanifestationsofthesomatizationtraitexpressedinthesepatients.”TheInternationaljournalofeatingdisorders.March1993

Thefoodintolerancesintheabovestudywereassessedsimplybyaskingpatientswhichfoodstheywereintolerant.InclassicalIgEallergy,foodscauseimmediateandobviousreactionswhichcaneasilybeself-identified,unlikeIgGreactionswhereidentificationoftheoffendingfoodismuchmoredifficultduetothedelayedreaction.

CFS/MEpatientsmayhavefailedtoimproveinthestudiesontheeffectsofdietaryrestrictionsquotedbelowbecauseallglutenorcross-sensitisedfoodswerenotadequatelyrestrictedandtherewerenospecificinterventiontohealthegutandreduceinflammation.

“A24-weekrandomizedinterventionstudywasconductedwith52individualsdiagnosedwithCFS.Patientswererandomizedtoeitheralowsugar,lowyeast(LSLY)orhealthyeating(HE)dietaryinterventions…

…Inthisrandomizedcontroltrial,aLSLYdietappearedtobenomoreefficaciousonlevelsoffatigueorQoLcomparedtoHE.”


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Inthe2012Trabalet.al.studyintheSpanishJournalNutriciónHospitalariatheauthorstookacrosssectionalpilotstudywith28patientsdiagnosedwithseverechronicfatiguesyndromeandassessedtheirdietaryeatinghabitswithfoodfrequencyquestionnaires.Theyreportedthat15patientswererestrictingglutenand22restricteddairyandtheyfound:

“Patientsreporteddifferentdigestivesymptoms,whichdidnotimprovewiththeuseofexclusiondiets,”andconcluded:

“Dietaryrestrictionsshouldbebasedonaprovenfoodallergyorintolerance.Dietarycounsellingshouldbebasedonsoundnutritionalknowledge.”

Despitethesenegativestudies,LoganandWongreportedonseveralstudieswheredietaryrestrictionsmadealargeimprovementinCFS/MEpatients:

Nisenbaumet.al.presentedanabstractattheAmericanAssociationforChronicFatigueSyndromeconferenceinSeattleinJanuary2001,showingthat54percentofasampleofCFSpatientshadattemptedunspecifieddietarymodifications.Oftheseindividualswhomodifiedtheirdiet,73percentreportedthedietarychangeswerebeneficialinreducingfatigue.InanAustralianstudy,CFSpatientseliminatedwheat,milk,benzoates,nitrites,nitrates,andfoodcoloringsandotheradditivesfromtheirdiet…OftheCFSpatientswhocomplied,theresultswereremarkable:90percentreportedimprovementintheseverityofsymptomsacrossmultiplebodysymptoms,withsignificantreductioninfatigue,recurrentfever,sorethroat,musclepain,headache,jointpain,andcognitivedysfunction.Furthermore,theeliminationprotocolresultedinamarkedimprovementinIBS-likesymptomsamongallpatients;asignificantfindingbecauseCFSpatientshaveahighrateofIBS.TheresultsofthisstudysupportthefindingsofBorokpublishedintheSouthAfricanMedicalJournaloveradecadeago.BorokcitedastrongcorrelationbetweenCFSandthepresenceoffoodintolerance.HereportedalleviationofchronicfatigueamongCFSpatients(n=20)afterremovingcertainfoodsfromthediet,withmilk,wheat,andcornamongthetopoffenders.”AlternativeMedicineReview2001

Atthemoment,nostudieshavebeendonetestingCFS/MEpatientscorrectlyforCDandNCGS,norhavetherebeenstudiestestingtheeffectivenessofintroducingastrictgluten-freedietandwithaguthealinganti-inflammatoryintervention.


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FACT 10: EveryPersonWithChronicFatigueSyndromeShouldBeScreenedforCoeliacDiseaseandNonCeliacGlutenSensitivityasPartoftheDifferentialDiagnosisoftheCondition

ManyfactorssuggestCDandNCGSshouldbepartofthedifferentialdiagnosisofCFS/ME.Neurologicalsymptomsarecommon.Backin1999,Luostarinenet.al.inEuropeanNeurology,statedthatCDshouldbeconsideredinallpatientspresentingwithneurologicaldisturbancessuchasmemorydeficitsandataxiaofunknownetiology.Small-fibreneuropathyandmusclepaincanbeinducedbyglutensensitivity.Symptomsofsmall-fibreneuropathysuchastingling,burningpainandtightness,stabbingpain,pinsandneedles,itchinessandintermittentnumbnessindifferentpartsofthebody,arecommonlyexperiencedinCFS/ME.Glutentriggeredautoimmunegangliosideantibodiescanproduceallthesesymptoms.

RituximabandotherstudiessuggestautoimmunityislikelytobepresentinasubgroupofCFS/MEpatients.ChronicdisorderssuchCDandNCGSwhichcauseBLymphocytesactivationcouldtriggerautoimmuneprocessesinthebody.SomeCFS/MEpatientscouldhaveimprovedwhenRituximabknockedoutglutentriggeredBlymphocyteactivation.

SeveralstudiessuggestCFS/MEisaninflammatorydisorder.Thelandmark2000Lancetstudythatidentifiednon-IgEmediatedfoodintolerancesdemonstratedthatindividualswithnon-IgEmediatedfoodintolerancehadsignificantelevationsininflammatorycytokines(interleukin-4,interferongamma,TNF-α)whengivenadietarychallengeofdairyandwheat.Theauthorsnotedthatcytokineelevationscouldaccountforthepost-challengesymptomsexperiencedsuchasheadache,myalgia,jointpain,andgastrointestinaldisturbance–allofwhicharecommoninCFS/ME.“Wefoundthatfoodprovocationinfoodintolerantpatientswascharacterisedbyageneralandsystemicimmuneactivationaccompaniedbyanincreaseinsystemicsymptoms.Ourfindingsmightbeimportantfortheunderstandingofthemechanismsinvolvedinthepathogenesisoffoodintolerance.”TheLancetJuly2000


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Othermoredirectlinkstocoeliacdiseaseandchronicfatiguesyndromeexist.CritiqueofthediagnosticcriteriaforCFS/MEaskedwhyrulingoutCDwasnotincluded.Skoweraet.al.foundahighprevalenceofmarkersofCeliacdiseasein100CFSpatientsin2001.“givenourprevalenceof2%,andthefactthatthereisatreatmentforCD,wenowsuggestthatscreeningforCDshouldbeaddedtotherelativelyshortlistofmandatoryinvestigationsinsuspectedcasesofCFS.”Skoweraet.al.2001Aswehavediscussed,sensitivitytoglutenislikelytobemuchhigherthan2%intheCFSpopulation,asCDischaracterizedbytotalvillousatrophyandthusmissesouttheglutensensitiveindividualswithpartialornovillousatrophy.We’vealsoshownthatamisseddiagnosisofglutensensitivityismoredangerousthanadiagnosisofCeliacdiseasesinceindividualswithglutensensitivity,butnotceliacdisease,willprobablymaintainastateofgutinflammationthatcantriggerneurological,autoimmuneandotherissues.ThisprobablyalsoexplainswhyanotherpreliminarypaperintheInternationaljournalofclinicalpracticein2001,foundnolinkbetweenCDandChronicFatigueSyndrome.Why You Probably Aren’t Getting this Information From Your Doctors WhyisceliacdiseasesolittlediscussedintheCFS/MECommunityoranyspecificAutoimmunegroup?ThesamereasonthatmanypatientsareprobablynotparticularlyawareofEhlersDanlosSyndromeorChiarimalformationormanyalternativehealthtreatments.

Firstofall,gastroenterologiststendtoreadJournalsdirectlyrelatedto,wellto…gastroenterology.Theydon’thavetimetoreadtheJournalsinHepatology,Immunology,PathologyorNutrition,andthereforetheyarenotconnectingthedotsandmissoutonvitalinformationthatdoesinfactrelatetotheirpracticesfromothermedicalspecialities.

ThissametheoryholdstruefornearlyANYautoimmunedisorder.NCGScanbeatriggerinover300autoimmunedisorders.

Second,Doctorsingeneralhavelimitedtimeandthereforefocusontheirspecialties,andmuchdoctoreducationcomesfromdrugcompanyrepresentativesshowingthemthepaperswhichsupporttheirlatestdrugtreatments.

Third,nutritionisnotgivenahighpriorityinmedicalschool.Ihavespent15yearscollatingandsynthesisingdataonglutensensitivity.Inmedicalschool,doctorsareonlyrequiredtocompletejust25hoursoftraininginnutrition.And:


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“Only28(27%)ofthe105MedicalSchoolsmettheminimum25requiredhoursofnutritioneducationsetbytheNationalAcademyofSciences;6yearsearlier,in2004,40(38%)of104schoolsdidso.”AcademicMedicine,Vol.85,No.9/September2010

Finally,someofthisinformationiscuttingedge,andcutting-edgeinformationcantakedecadestofilterdownfromtheresearchfieldtothestandardphysician’soffice.Inthe1970sitwasestimatedthetimeittookforpublishedresearchtobeappliedinclinicalpracticewithpatientswasabout65years!Withtheinternet,thishasprobablymorethanhalved.

Inconclusion,it’snotyourDoctor’sfault–she/heisoverworkedasitisandisdealingwithanalreadyverycomplexdisorder.Theycan’tbeexpectedtobeontopofeverything.Therefore,asweallknow,it’sbesttogeteducated,takethisinformationtoyourDoctorifneededanddon’twaitaroundfor30yearsbeforeyourDoctorsfinallygiveYOUtheinformation.

How Do I Get Tested? First,havethebloodtestdoneforCD.Ifthatcomesbacknegative,checkforNCGSfirstbyArray#3antibodytestingfromCyrexLabs.Ifthat’snotavailable,atrialperiodofeliminatingglutenisrational.

Ifyouarehavinganendoscopy/biopsydone,requestthatanIEL(Intraepitheliallymphocytes)countbedonetoassessinflammationinthegut.Mostpathologistsdon’tdoitbutit’seasyandinexpensive(about$40).Thistestwilldetermineifyoufallintotheinflammatorysub-clinicalgroupofNCGSpatients.

IftheArray3comesbackpositive,youcanthenrequestArray4fromCyrexlabstotestforcross-sensitizedfoods.Thelabautomaticallysavestheoriginalbloodsamplefor3monthssoanotherbloodsampleisnotneeded.

Youmayalreadyknowyouhavesomeformofglutensensitivity;toconfirmthis,dothesametestasabove.Note:don’tworryifyouhavenoteatenglutenbeforedoingthetestanddon’tgobackonglutenforthetestbecauseitcanhaveveryadverseeffectsonsomepatients.Muchofthetime,evenifyouthoughtyouweregluten-free,you’veprobablystillbeenexposed,unknowinglyandthistestingwillconfirmthat.

IntheUKandEuropeRegenerusLabsoffertheCyrexLabstesting.Checkbackoftenforupdatesforotherlocationsaroundtheglobewheretestingmaybeavailable.

What Can I Do To Determine if I have Celiac Disease or Non-Celiac-Gluten Sensitivity?


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How Do I Follow a Gluten-Free Diet? Animportantfactisthatmortalityratesriseafterthefirstyearofgoinggluten-freepossiblyduetoglutenwithdrawalandbecausebloodsugarproblemsariseassomepeoplestarttoskipmeals.CardiovasculardiseasewasthemostcommoncauseofdeathinCoeliacdisease,followedbymalignancy.ThehighestHRswereseeninthefirstyearafterbiopsy,withanHRof3.78fordeathduetomalignancyand1.86forCVdeath.JournaloftheAmericanMedicalAssociation.

Irecommenda“modifiedgluten-free”diet,whichisessentiallyagluten-freedietdesignedtomanagebloodsugarimbalancesandthecrasheswhichoftenoccurintheearlywithdrawalphasefromgluten.Alowsugardiet,mealsfivetimeperdayandotherstandardrecommendationstomanagebloodsugarlevelsareneededtopreventbloodsugarfallingtooloworrisingtooquicklyleadingtocrashes.

Followingagluten-freedietwhereeventhatcroutoninyoursaladcancauseproblemstakestimetomaster.Didyouknowglutenispresentincosmeticsandpersonalhygieneproductstoo?Theglutendoesn’tgenerallygothroughyourskin(unlessithasbeenthroughnano-technology),insteaditgetsinhaledwithsimilaradverseeffectsasoralconsumption.

Formoredetailsofmyproductsandfurthersupportonmovingtoagluten-freedietseehttp://glutenfreelearning.com/orhttp://theDr.com/

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