Il Mal Di Glutine - Fonti Bibliografiche

Celiachia silente e problemi della gravidanza

Caramaschi P, Biasi D, Carletto A, Randon M, Pacor ML, Bambara LM., [Celiac disease and abortion: focusing on a possible relationship], Recenti Prog Med 2000 Feb;91(2):72-5 Ciacci C, Cirillo M, Auriemma G, Di Dato G, Sabbatini F, Mazzacca G., "Celiac disease and pregnancy outcome", Am J Gastroenterol 1996 Apr;91(4):718-22 . Gastroenterology, Medical School, Naples University "Federico II," Italy

Collin P, Vilska S, Heinonen PK, Hallstrom O, Pikkarainen P., "Infertility and coeliac disease", Gut 1996 Sep;39(3):382-4 . Department of Medicine, University of Tampere, Finland) De Sandre G, Caramaschi P., "Untreated celiac disease with bad outcome of three pregnancies followed by a fourth normal pregnancy after two years of gluten-free diet", Am J Gastroenterol. 1996 Dec;91(12):2653

Eliakim R, Sherer DM., "Celiac disease: fertility and pregnancy", Gynecol Obstet Invest 2001;51(1):3-7 ABSTRACT (Division of Gastroenterology, Rambam Medical Center, Technion School of Medicine, Haifa, Israel) Martinelli P, Troncone R, Paparo F, Torre P, Trapanese E, Fasano C, Lamberti A, Budillon G, Nardone G, Greco L., "Coeliac disease and unfavourable outcome of pregnancy", Gut 2000 Mar;46(3):332-5 Department of Obsetrics and Gynaecology, University of Naples Federico II, Naples, Italy.

Ferguson R, Holmes GK, Cooke WT., "Coeliac disease, fertility, and pregnancy", Scand J Gastroenterol 1982 Jan;17(1):65-8

Ogborn AD., "Pregnancy in patients with coeliac disease", Br J Obstet Gynaecol 1975 Apr;82(4):293-6 Page 1 of 399

Sher KS, Jayanthi V, Probert CS, Stewart CR, Mayberry JF., "Infertility, obstetric and gynaecological problems in coeliac sprue", Dig Dis 1994 May-Jun;12(3):186-90

Sher KS, Mayberry JF., "Female fertility, obstetric and gynaecological history in coeliac disease: a case control study", Acta Paediatr Suppl 1996 May;412:76-7

Smecuol E, Maurino E, Vazquez H, Pedreira S, Niveloni S, Mazure R, Boerr L, Bai JC., "Gynaecological and obstetric disorders in coeliac disease: frequent clinical onset during pregnancy or the puerperium", Eur J Gastroenterol Hepatol 1996 Jan;8(1):63-89

Stazi AV, Mantovani A., "A risk factor for female fertility and pregnancy: celiac disease", Gynecol Endocrinol 2000 Dec;14(6):454-63

Stazi AV, Mantovani A., [Celiac disease. Risk factors for women in reproductive age], Minerva Ginecol 2000 May;52(5):189-96 Istituto Superiore di Sanita, Laboratorio di Tossicologia Comparata ed Ecotossicologia, Roma. avelia@iss;it In the past coeliac disease, or intolerance to gluten, has been considered a rare disease in infancy, whose most important signs were chronic diarrhea with malabsorption and reduced growth. However, besides this classical form, there are a number of other clinical and subclinical forms which may appear even in the adult life and without any overt intestinal sign. The alterations may affect, e.g., the liver, thyroid, skin and the female and male reproductive system. The overall prevalence of the different forms of coeliac disease in Western Europe is at least Page 2 of 399

1:300. The aim of the present paper is to describe and evaluate the effects of coeliac disease on female reproduction. Such effects include delayed menarche, amenorrhea, infertility and early menopause. Epidemiological studies show that besides reduced fertility, affected women are at higher risk of reproductive problems such as pregnancy loss, low birthweight of offspring and reduced duration of breastfeeding. There are no adequate studies to evidentiate a possible increase of birth defects; nevertheless, coeliac disease induces malabsorption, with deficiencies of nutritional factors essential to prenatal development such as iron, folic acid and vitamin K. The mechanisms underlying the reproductive alterations are still awaiting clarification; however, an interaction among specific nutritional deficiencies, endocrine imbalances and immune disturbances is suspected. As for the other effects associated to the coeliac disease, the possible prevention or treatment of the reproductive effects is only the lifelong maintenance of a glutenfree diet.

Sher KS, Mayberry JF., "Female fertility, obstetric and gynaecological history in coeliac disease. A case control study", Digestion 1994;55(4):243-6 Gastroenterology Research Unit, Leicester General Hospital, UK. The purpose of this study was to investigate the incidence of infertility, abortions and perinatal mortality, age at menarche and menopause in coeliac disease (CD). It was a case control study in which patients and controls matched for age and sex were sent questionnaires about their fertility profile and other obstetric and gynaecological problems. All 80 patients and 70 controls replied but only 68 groups could be matched for this study. The mean age of menarche in patients was significantly older at 13.6 years than in controls at 12.7 years. The mean age at menopause in patients and controls were 47.6 and 50.1 years respectively. The study showed the mean number of children born to patients with CD was significantly less at 1.9 (SD +/- 0.9) compared to 2.5 (SD +/- 1.2) in controls. Before diagnosis the mean number of children born to patients was 1.4 and 1.8 in controls. After diagnosis and treatment, patients had 0.5 children (SD +/- 0.9) compared to 0.7 in controls (SD +/- 1.2). It seems likely that the overall difference in fertility is due to relative infertility prior to diagnosis and its correction by a gluten-free diet. Significantly more conceptions amongst women with CD (15%) ended in miscarriage prior to diagnosis than amongst controls (6%). After diagnosis and treatment the rate of miscarriage was similar at 7 and 12% respectively. There were Page 3 of 399

120 live babies and 7 stillbirths to patients compared with 161 live babies and 1 stillbirth to controls. In conclusion, this study shows that patients with CD are subfertile and have an increased incidence of stillbirths and perinatal deaths.

Zajadacz B, Kucko W, Juszkiewicz A.,[Menstruation disturbances in a 17-year-old girl with coeliac disease] Wiad Lek 2000;53(7-8):466-8 ABSTRACT (Oddzialu Dzieciecego Wojewodzkiego Szpitala w Gorzowie Wielkopolskim) The case of 17 year old girl with coeliac disease and menstruation disturbances was described. The patient began to menstruate regularly at the age of 15 during gluten-free diet. After the change to gluten diet bleedings occurred every 10 days. When she again went on free-gluten diet regular menstruations came back. These disturbances may be connected with introducing gluten to the diet.

Alopecia e allergia al glutine

Barbato M, Viola F, Grillo R, Franchin L, Lo Russo L, Lucarelli S, Frediani T, Mazzilli MC, Cardi E., "Alopecia and coeliac disease: report of two patients showing response to gluten-free diet", Clin Exp Dermatol. 1998 Sep;23(5):236-7. No abstract available.

Di Maita M, Amantia L, Morana G., [Association of uveitis, alopecia and celiac disease], Ophtalmologie. 1987 Jul-Sep;1(3):401.

Naveh Y, Rosenthal E, Ben-Arieh Y, Etzioni A., "Celiac disease-associated alopecia in childhood", J Pediatr 1999 Mar;134(3):362-4 Page 4 of 399

We report the association of celiac disease and alopecia in 3 children. In one, the alopecia developed after 4 years' nonadherence to a gluten-free diet; the other 2 patients presented with alopecia. Administration of a gluten-free diet resulted in partial regrowth of hair in the first child and complete hair growth in the others.

ANEMIA e MALASSORBIMENTO

Indagini nei casi di grave anemia - L'anemia può essere definita come valori di emoglobina minori di 7.4 mmol/l nelle donne e sotto 8.0 mmol/l negli uomini. Si parla di carenza di ferro se una delle seguenti condizioni è presente: a. livello di ferritina minore di 20 ng/l per gli uomini e minore di 10 ng/l per le donne, b. ferro sierico inferiore a 45 ng/dl (8.1 nmol/l) con una saturazione di transferrina minore del 10% o c. assenza di riserve di ferro in campioni di biopsie del midollo osseo

Sanguinamenti gastrointestinali sono una nota causa di anemia. La valutazione standard di un paziente con anemia include una indagine completa del tratto gastrointestinale per identificare eventuali fonti di sanguinamento, che possono essere ulcere e perforazioni o altre emorragie gastrointestinali, gastriti collagenose o tumori gastrointestinali. Solo dopo aver effettuato esofagogastroduodenoscopia e colonoscopia, e se non si sono avuti riscontri di alcun tipo da queste valutazioni, sta diventando sempre più indicato fare enteroscopie con prelievo di biopsia intestinale per valutare la possibilità di celiachia. La celiachia è un'altra nota causa di gravi anemie. Un'altra nota causa di carenza di ferro potrebbero essere gravi stati di malassorbimento intestinale, che non sfociano in celiachia evidente e rilevabile. Alterazioni morfologiche correlate con malassorbimento intestinale di ferro possono anche essere dovute a giardia, diverticolosi ed altre infestazioni intestinali. Page 5 of 399

Un esempio Vediamo un caso clinico riportato da Schmitz (1994): "Paziente 40enne con anemia cronica di origine ignota. Le valutazioni mediche si erano succedute per 2 anni senza riuscire a risalire alla causa. Gli esami endoscopici non avevano rivelato anomalie macroscopiche della mucosa gastrointestinale. L'uso di supplementi di ferro non aveva avuto alcun effetto sui livelli di ferro nel sangue e sull'anemia. Ripetiamo presso l'ospedale dell'università di Bonn l'endoscopia, ma neanche questo nostro esame rivela anomalie macroscopiche. Le biopsie del tratto superiore gastrointestinale rivelano invece atrofia incompleta dei villi nel piccolo intestino. Una dieta senza glutine porta ad un aumento del ferro nel sangue, alla guarigione dell'anemia e della morfologia della mucosa". L'anemia è una caratteristica comune in pazienti con celiachia e, in molti di essi, può essere il solo segnale clinico. Biopsie intestinali per individuare la celiachia, purtroppo, non sono usate di routine nei casi di anemia, segnala Ackerman nel 1996, che aggiunge: "Un consistente numero di pazienti israeliani adulti con anemia risultarono, avviata l'indagine specifica, avere anomalie della mucosa gastrointestinale compatibili con la diagnosi di celiachia. L'accertamento di esofagite, gastrite o duodenite mediante esofagogastroduodenoscopia, ed anche altre anomalie accertate con la colonsciopia non fanno escludere la coesistenza con la celiachia".

Vediamo un altro esempio. Un caso in cui l'anemia era il solo sintomo di celiachia (Solana-de Lope, 2000). L'endoscopia del tratto alto gastrointestinale, la colonscopia e le prove di contrasto con bario del piccolo intestino erano risultate normali. Persino gli anticorpi relativi alla celiachia, antiendomisio e antireticolina erano risultati negativi. Infine furono individuati anticorpi IgA alla gliadina e atrofia dei villi mediante enteroscopia. Dopo 4 mesi di trattamento con dieta senza glutine i livelli di emoglobina e ferro nel sangue si normalizzarono e lo stesso avvenne per la morfologia della mucosa.

Anemia da celiachia I medici dovrebbero essere attenti e pronti alla possibilità di celiachia negli anziani, in particolare in pazienti con sintomi non specifici in presenza di inspiegabile anemia. Queste situazioni Page 6 of 399

scompaiono con una dieta senza glutine e dunque è inammissible trascurare la valutazione di tale opzione (Hankey 1994). La celiachia induce un'alterazione della morfologia della mucosa intestinale e dunque malassorbimento, primi tra tutti di ferro, poi di acido folico e di vitamina K (Stazi 2000). Rea (1996) documenta anomali bassi valori di emoglobina, ferro e zinco sierici al momento della diagnosi della celiachia in più della metà dei pazienti, ma tutti questi valori ritornava alla normalità, insieme alla morfologia dei villi intestinali, dopo un anno di dieta senza glutine. Lazzari (1994) documenta che su un campione di 212 pazienti con celiachia, 103 avevano anemia al momento della diagnosi. L'assorbimento di Fe2+ risulta ridotta nella celiaci che continuano a consumare glutine, a causa dello stato alterato della mucosa intestinale. Questi sono risultati di test di assorbimento fatti già nel 1977 da Anand su pazienti che continuavano a consumare glutine e su quelli che lo sospendevano. Sia lo stato della mucosa sia l'assorbimento di ferro miglioravano con una dieta senza glutine. Nel 50% dei pazienti celiaci può essere evidenziato un sanguinamento gastrointestinale occulto, e ciò dovrebbe essere aggiunto alla lista dei fattori che possono contribuire a carenze di ferro in tali pazienti, cioè malassorbimento del ferro nella dieta o alla perdita di ferro dalla mucosa intestinale (Fine, 1996). Occulte perdite di sangue scomparivano nei pazienti celiaci che sospendevano il consumo di glutine (Shamir 2000). Nella celiachia, quando la maggior parte o tutta la mucosa intestinale sarà coinvolta, i sintomi saranno gravi e il malassorbimento generalizzato. In questi casi clinici ben definiti la possibilità di celiachia e dunque gli esami specifici saranno più prontamente presi in considerazione. Nel caso invece di lesioni della mucosa limitate al duodeno, evidenti sintomi gastrointestinali e steatorrea saranno assenti. In questi pazienti le manifestazioni cliniche, quando ve ne sono, possono riflettere il malassorbimento di solo una o due sostanze, in particolare ferro e acido folico, che sono assorbiti in qualche modo selettivamente nella prima parte dell'intestino (Trier 1993) Foller (1993) descrive 3 pazienti che presentavano isolate manifestazioni di malassorbimento ma senza i tipici sintomi di celiachia, come diarrea e steatorrea. Questi pazienti avevano un'anemia da ferro che non migliorava con l'uso di supplementi. Trovati gli anticorpi della celiachia e verificata l'atrofia dei villi intestinali da prelievi istologici, fu adottato un regime alimentare senza glutine che portò alla scomparsa dei sintomi. Uno studio pubblicato da Depla nel 1993 si intitola: "Anemia: presentazione di celiachia monosintomatica". Scrive Depla: "Descriviamo 3 casi di anemia senza altri sintomi nei quali la celiachia fu presa in considerazione e diagnosticata molti anni dopo la comparsa clinica dell'anemia". I pazienti con celiachia monosintomatica possono eludere la diagnosi per molto Page 7 of 399

tempo. L'anemia è uno dei più comuni riscontri nella celiachia, però l'anemia come solo sintomo spesso non conduce ad un'immediata indagine sulla possibilità di celiachia.

Kaiser (1991) presenta il caso di una paziente 23enne che, senza altri sintomi e con peso normale, aveva avuto per almeno due anni una anemia da ferro. La radiografia del piccolo intestino aveva rivelato una modalità anomala con ruvida rugosità del duodeno. Biopsia duodenale ottenuta endoscopicamente aveva dimostrato atrofia dei villi. La presenza di anticorpi alla gliadina aveva confermato la diagnosi di celiachia monosintomatica, cioè la cui unica manifestazione era l'anemia. La paziente guarì completamente dall'anemia con un regime senza glutine. Vivaldi (1995) presenta il caso di una donna affetta da anemia sideropenica per circa 30 anni, senza che regolari iniezioni endovenose di ferro potessero ripristinare il suo strato di carenza. Solo all'età di 30 anni apparve una sindrome di malassorbimento da cui si scoprì e diagnosticò la celiachia. Con la sospensione del glutine si ebbe la guarigione dall'anemia. L'anemia sideropenica c'era stata dall'inizio ed aveva continuata per anni ad essere il solo sintomo di malassorbimento. "Quando l'anemia sideropenica è resistente al trattamento con iniezioni di ferro", conclude il ricercatore, "dovremmo sempre sospettare un malassorbimento dovuto a celiachia". Sari (2000) descrive 2 casi di celiachia asintomatica che per 3 anni avevano presentato inspiegabile grave anemia da ferro. L'uso di supplementi di ferro non avevano corretto i loro livelli di ferro ed emoglobina nel sangue. Una dieta senza glutine portò ad un aumento del ferro nel sangue, scomparsa di anemia e normalizzazione della morfologia della mucosa. Dunque, conclude Sari, "anche le più gravi anemie da ferro, correlate con celiachia asintomatica, rispondono ad una dieta senza glutine". Straub e collaboratori presentano 2 casi clinici di grave anemia sideropenica nei quali l'indagine specifica e dunque la diagnosi finale di celiachia fu effettuata solo dopo molti anni dalla diagnosi di anemia. A conferma di questa situazione ci fu una completa normalizzazione dei valori di emoglobina quando i pazienti adottarono una dieta senza glutine. Gli autori concludono: "L'obiettivo di questo studio è stato di portare l'attenzione all'eventualità di malassorbimento selettivo di ferro e dunque anemia sideropenica come la sola manifestazione clinica del malassorbimento nella celiachia. Ciò dovrebbe essere sospettato quando l'esame delle perdite di sangue risultano futili e quando la somministrazione di ferro non produce effetti". Un paziente con anomalie dei valori ematologici fu trattato prima con supplementazione di vitamina B12 e acido folico, poi con supplementi di ferro ma senza successo. Infine fu valutata la possibilità di celiachia e, nonostante l'assenza delle classiche manifestazioni gastrointestinali quali steatorrea e diarrea, questa fu confermata dagli specifici esami (Cordum 1995). Cordum conclude che un'inspiegabile carenza di ferro dovrebbe allertare il medico della possibilità di celiachia. Page 8 of 399

Una donna 70enne fu ricoverata in ospedale dopo una storia clinica di 5 anni con perdita di peso, indebolimento, anemia, osteomalacia e dolori che ripsondevano solo ad analgesici narcotici (Monti 1996). Il test di assorbimento dello xilosio mostrò uno stato di malassorbimento e dunque il test degli anticorpi antigliadina e antiendomisio evidenziò celiachia, confermata da accorciamento o assenza dei villi intestinali. Monti conclude che casi atipici di celiachia senza i classici sintomi gastrointestinali stanno aumentando sempre più e un'anemia persistente nonostante supplementi di ferro o l'osteomalacia possono essere i soli sintomi osservabili. Facendo uno screening di donatrici di sangue Unsworth (2000) scopre 32 casi con anticorpi della celiachia di cui 29 avevano anemia microcitica. "In nessuno di questi casi, prima del nostro intervento, la possibilità di celiachia era stata investigata". Cioè la celiachia è sotto diagnosticata e sotto investigata in pazienti anemiche. Stahlberg (1991) segnala che in 54 bambini finlandesi al momento della diagnosi di celiachia c'era lieve anemia da ferro o comunque carenza di ferro. Sospendendo il glutine, anche senza l'uso di supplementi di ferro, spariva ogni evidenza di carenza di ferro e si normalizzavano completamente tutti i valori di laboratorio. Una susseguente reintroduzione del glutine portava ad una rapida ricomparsa di valori alterati di ferro e di ferritina ematica. 80 bambini celiaci furono divisi da Bonamico e collaboratori (1987) dell'università La Sapienza di Roma a secondo che avessero attivo alterata meorfologia dei villi e se seguissero una dieta senza glutine. Il 51% dei pazienti con atrofia della mucosa e il 56% dei bambini che consumavano glutine avevano livelli di ferro nel sangue minori di 50 microgrammi/dl; il 35% dei pazienti di entrambi i gruppi avevano ferritina sierica minore di 12 microgrammi/L. Dall'altra parte, solo una piccolissima parte dei bambini con mucosa normale e con regime senza glutine mostrarono il quadro subclinico di carenza di ferro.

Bulfoni (1995) riporta il caso di una paziente 23enne per la quale una grave anemia da ferro era stata la sola manifestazione clinica della celiachia. Sospendendo il glutine l'anemia scompariva. Una grave deficienza di ferro fu la manifestazione clinica in un paziente con celiachia che per molto tempo non fu sospettata e identificata nonostante le visite mediche (Brady 1994). In una paziente 21enne per molti mesi l'anemia fu il solo sintomo di quella che poi verrà diagnosticata celiachia mediante gli specifici esami (Jankovska 1993). La letteratura abbonda di rapporti di simili casi di celiachia monosintomatica (solo con anemia). Un paziente con anemia, neutropenia e ipersegmentazione granulocitica viene trovato essere positivo all'esame sierologico e istologico per la celiachia. Le anomalie ematologiche si risolsero entro 3 settimane seguendo una dieta senza glutine (Pittschieler 1995). Page 9 of 399

Dickey (1996) spiega che la percezione generale di rarità di celiachia riflette il fenomeno della scarsa prontezza a diagnosticarla. L'anemia spesso è la sola manifestazione clinica della celiachia. 17 casi sono presentati da Dickey (1996). L'autore descrive 14 pazienti in cui, nonostante numerosi esami e visite, la diagnosi di celiachia fu fatta con notevole ritardo, per 9 di questi pazienti dovettero passare più di 6 anni di valutazioni. Altri casi in cui la carenza di ferro era stato il primo sintomo della celiachia sono riportati da: Zieleznik 1968, Kilpatrick 1969, McNeish 1969, Plochl 1969, Sutton 1970, Singh 1970, Socha 1970, Sutton 1971, Brown 1975, Harms 1976, Proctor 1976, Kastrup 1977, Cooper 1979, Kosnai 1979, Telesz 1981, Braide 1982, Bardella 1985, Rosenbach 1986, Bosch 1990, Bouguerra 1990, Korman 1990, Encinas Sotillos 1991, Harle 1991, Rashid 1991, Denman 1992, Andant 1993, Gostout 1993, Jankovska 1993, Hamrick 1994, Malave 1994, Sanderson 1994, van Bergeijkl 1994, Leber 1995, Santos 1996, Strauch 1996, Macdonald 1996, Barton 1997, Diaz Diaz 1997, Goddard 1997, Callejas Rubio 1998, Calvo Romero 1999, Fernandez Rodriguez 1999, Gutierrez Junquera 1999, Hermo 1999, Kariv 1999, Wallace 1999, Yenerel 1999, Pearce 2001. L'evidenza clinica di carenza di ferro ed emoglobina sierica può essere usato come punto di riferimento per arrivare alla diagnosi di celiachia. La celiachia, sottolinea Volpe (1997), può causare un malassorbimento selettivo e dunque una presentazione clinica non immediatamente identificabile. Volpe presenta due casi di celiachia nei quali le indagini specifiche erano state spronate da inspiegabili anemie croniche. In una valutazione di pazienti con anemia ferropenica, Garrido (1997) riporta tra i pazienti con anemia una certa prevalenza di celiachia non diagnosticata la cui unica presentazione era stata una forte carenza di ferro. Garrido invita dunque ad usare sempre lo strumento dello screening della celiachia nei casi in cui non ci siano evidenti lesioni all'esame endoscopico. Valutando 25 pazienti con anemia sideropenica che non rispondeva a trattamenti con ferro, in 5 fu riscontrata atrofia dei villi intestinali (Carroccio 1998). Durante uno screening di pazienti con anemia ipocromica, Ciacci (1999) scopre in 10 pazienti una celiachia che nessuno prima di allora aveva mai sospettato. Lazzari aveva avuto gli stessi risultati nel 1994: "Il nostro studio dimostra che una certa percentuale di pazienti affetti da anemia ipocromica di eziologia ignota possono essere affetti da celiachia". Uno studio pubblicato da Dickey nel 1997 si intitola: "Biopsie gastriche e duodenali possono rivelarsi utili nella valutazione dell'anemia". In 8 casi su 40 di anemia, senza specifici sintomi gastrointestinali, fu rilevata atrofia dei villi intestinali. "I nostri risultati", scrive Dickey nel 1997, "confermano l'importanza di ricercare la celiachia in pazienti con anemia. In particolare le biopsie duodenali dovrebbero essere prese in considerazione anche in assenza di ancticorpi sierici della celiachia". Page 10 of 399

16 casi di celiachia precedentemente con diagnosticata vengono riportati da Corazza (1995) nel suo studio tra pazienti anemici che risultarono avere gli anticorpi antigliadina. Concludendo, ricorrenti inspiegabili anemie sono un'indicazione per la ricerca di celiachia mediante biopsie intestinali (Mainguet 1992).

Alterazioni mucosa intestinale e carenza di ferro nella celiachia Annibale (2001) ha sottoposto a screening della celiachia 190 pazienti con anemia senza altri sintomi. Dopo aver riscontrato 26 casi di atrofia dei villi intestinali (celiachia), in questi pazienti veniva adottata una dieta senza glutine. Il recupero delle donne con celiachia fu seguito da vicino: dopo 6 mesi di dieta senza glutine il 77.8% si erano riprese dall'anemia (emoglobina sierica), ma solo il 27.8% avevano risolto la carenza di ferro; dopo 12 mesi il 94.4% avevano recuperato dall'anemia e il 50% dalla carenza di ferro. Le conclusioni di Annibale e collaboratori sono queste: "Una valutazione sistematica della celiachia dovrebbe essere condotta in pazienti adulti con anemia. La guarigione dall'anemia avviene tra i 6 e i 12 mesi di dieta senza glutine, come conseguenza della normalizzazione delle alterazioni della mucosa intestinale". Souroujon (1982) ci dà delle indicazioni interessanti. Egli ci dice che pazienti celiaci che non abbiano escluso il glutine dalla dieta spesso hanno bassissimi livelli di ferritina che aumentano ad una velocità media di 1 microgrammo/1 al mese quando si adotta una dieta senza glutine. Quando il paziente torna ad una dieta con glutine, però, i livelli di ferritina diminuiscono rapidamente ad una velocità di circa 4 microgrammi/1 al mese. "C'è sicuramente una correlazione tra anomali alterazioni intestinali e bassi livelli di ferritina nei celiaci con un miglioramento di entrambi quando il paziente passa ad un regime senza glutine", conclude Souroujon (1982). Nel caso di 20 bambini celiaci Hjelt (1990) monitorò la concentrazione di ferro in periodi di sospensione di glutine e in periodi di consumo di glutine. La concentrazione di ferro nel sangue cresceva, andando verso la normalizzazione, nel momento in cui si sospendeva il glutine. Pare e collaboratori (1988) segnalano che nella celiachia attiva risultano quasi sempre alterati i livelli delle riserve di ferro (88%) e di folato nei globuli rossi (82%), o entrambi (74%), e dunque questi esami, presi in serie, insieme con i rilievi radiografici che rivelano anomalie del piccolo intestino (83%), potrebbero essere addirittura usati in alternativa alla invasiva enteroscopia con biopsia, per monitorare la regressione della malattia dopo la sospensione del glutine.

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Anemie ricorrenti inspiegabili possono preannunciare una mucosa pre-celiaca? Egan-Mitchell (1991) presenta un caso molto significativo nel quale la mucosa duodenale è normale, normale sono i linfociti inter-epiteliali, la fosfatasi alcalina e la sucrasi, nomale il test con lattosio e xilosio. Si tratta di una bambina con ritardo nella crescita e con carenza di ferro da 2 anni. L'attività delle lattasi della mucosa era bassa. Solo 14 mesi dopo questi primi esami, furono evidenziate alterazioni della mucosa consistenti con la celiachia. Egan-Mitchell trae le seguenti conclusioni da questo studio: "E' probabile che in alcuni bambini le lesioni della mucosa relative alla celiachia avvengano molto gradualmente, così che ci sia uno stadio iniziale con morfologia normale e solo poche anomalie, come la soppressione dell'attività della lattasi e possibilmente interferenza con l'assorbimento di ferro. Dorst (1998) presenta la storia clinica di una 67enne cui nel corso di 20 anni con numerosi ricoveri in ospedale era stata fatta la diagnosi di anemia da ferro, disfunzione dell'assorbimento di ferro, osteoporosi e iperparatiroidismo. Appunto, solo dopo 20 anni, fu scoperto che aveva celiachia. Iniziò una dieta senza glutine che le portò uno straordinario miglioramento. Una donna 38enne fu diagnosticata con una grave anemia nel 1983. 8 anni dopo essa sviluppò i classici sintomi di celiachia, cioè diarrea, perdita di peso ed appetito diminuito. Questo caso viene presentato in un articolo di Glikberg (1995).

Se è vero che in alcuni pazienti adulti c'è una fase di transizione verso la celiachia, tra gli stati di subclinico malassorbimento quello predominante, e dunque da tenere ben presente, è la carenza di ferro ed emoglobina sierica.

Volendo sorvolare sui casi clinici di piena celiachia (infatti la celiachia negli adulti rimane senza diagnosi per anni anche in presenza di sintomi e valori ematici evidenti e inspiegabili in altro modo), vediamo che il peregrinaggio di pazienti con celiachia in via di progressione può durare in media 20 anni e più (Hankey 1994). 38 di questi pazienti celiaci, dopo un peregrinaggio ventennale, adottarono una dieta senza glutine con risoluzione dei sintomi, cioè dopo un anno di sospensione del glutine si registrò un notevole miglioramento in peso, nei valori di emoglobina, albumina, calcio e fosfatasi alcalina.

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Malassorbimento ed anemia Abbiamo detto che un'altra nota causa di carenza di ferro potrebbero essere gravi stati di malassorbimento intestinale, che non sfociano in celiachia evidente e rilevabile.

Ercan (1991) evidenzia, attraverso esame istologico su biopsie intestinali, che in 11 bambini con anemia da ferro c'erano diversi gradi di anomalie morfologiche della mucosa, dal danno ai villi a scendere fino ad un'aumentata attività criptica, un'aumentata infiltrazione linfoplasmocitica e alterazioni della superficie epiteliale. Evidenziabile poi dalle biopsie a livello ultrastrutturale, erano lesioni dei microvilli, alterazioni mitocondriali ed un aumento nei lisozomi. I test di carico con ferro e xilosio evidenziavano un certo grado di malassorbimento in alcuni pazienti, che fu possibile correlare con le alterazioni strutturali.

In uno studio su 50 anziani il malassorbimento intestinale emerse come una significativa causa di bassi livelli di ferro sierico, di emoglobina e calcio (Montgomery 1978). Il test di carico dello xilosio era stato usato come utile procedura di screening per valutare il malassorbimento intestinale. Anche nei bambini è evidenziabile la correlazione tra malassorbimento e anemia (Vetrella, 1974).

L'anemia, il malassorbimento e la steatorrea sono le manifestazioni cliniche più comuni di una malattia chiamata sindrome di Anderson, caratterizzata da anomalie nel trasporto di grassi attraverso la mucosa intestinale. Alterazioni della morfologia della mucosa intestinale sono evidenziabili, ma senza la atrofia peculiare nella celiachia (Lacaille 1989).

Un malassorbimento di ferro che andava da lieve a moderato è segnalato in pazienti con dermatite erpetiforme, sindrome che qualche volta coincide con la celiachia, ma non sempre (Kastrup 1977).

De Vizia 1992 riporta che la carenza di ferro era comune in 199 bambini affetti da stati di malassorbimento, in particolare con intolleranza al glutine (84%) o intolleranza al latte (76%),

Anomalie dei villi intestinali possono sfociare in tetania, una forma subclinica di celiachia con grave malassorbimento. Cano Ruiz (1996) riporta alcuni casi clinici di inspiegabile anemia Page 13 of 399

cronica e conclude che in casi di isolata tetania o inspiegabile resistente anemia bisogna andare a valutare l'intolleranza al glutine che potrebbe essere alla base dello stato di malassorbimento.

Infestazioni intestinali De Vizia (1985) presenta 10 bambini con infestazione da Giardia, 8 dei quali avevano carenza di ferro, e tra questi 3 presentavano l'anemia come il principale problema. Il malassorbimento intestinale di ferro fu confermato da appositi test di carico. In contrasto, nei 2 pazienti con normali livello di ferro il test di carico con il ferro evidenziava un normale assorbimento. Il test di carico con lo xilosio evidenziava un malassorbimento in 5 degli 8 pazienti con carenza di ferro. Dopo aver trattato farmacologicamente ed eliminato la Giardia svaniva anche lo stato di malassorbimento. Paralleli studi morfologici con biopsia intestinale rivelarono moderati cambiamenti della mucosa intestinale in 2 pazienti.

Su 40 pazienti con infestazione intestinale con giardia o con crescite parassitiche, Gheorghescu e collaboratori (1976) riscontrano 15 casi di lesioni morfologiche della mucosa intestinale e carenza di ferro. Dopo 6 mesi di trattamenti farmacologici per la giardia, l'aspetto morfologico della mucosa intestinale migliorò significativamente, anche i valori serologici di ferro, indicando il ruolo patogeno dei parassiti intestinali nello sviluppo del malassorbimento selettivo.

Diverticolosi del piccolo intestino in 3 pazienti con anemia da ferro viene segnalata da Pras (1984). Sulla base di questi casi clinici e della letteratura medica disponibile, l'autore conclude che la diverticolosi del piccolo intestino può portare ad anemia da ferro mediante cronica perdita di sangue. Secondo Savino (1982), diverticoli di Meckel con associata stagnazione e proliferazione batterica possono portare ad alterazione metaboliche di alcuni elementi e persino lesioni gravi della mucosa ileale.

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atassia_g

Finelli PF, McEntee WJ, Ambler M, Kestenbaum D Adult celiac disease presenting as cerebellar syndrome. Neurology 1980 Mar;30(3):245-9

A progressive pancerebellar syndrome in a 57-year-old man heralded what was subsequently diagnosed by malabsorption studies and jejunal biopsy as adult celiac disease. Postmortem examination demonstrated characteristic gastrointestinal and cerebral abnormalities associated with this enteropathy. The neuropathology underlying the ataxia, as well as the clinical features of palatal myoclonus and marked speech impairment, included marked cerebellar cortical atrophy with cell loss in dentate and olivary nuclei. Intestinal-absorption studies are indicated to evaluate patients with any neurologic illness that may be related to malabsorption.

Ciacci

Pellecchia MT, Scala R, Perretti A, De Michele G, Santoro L, Filla A, Ciacci C, Barone P., "Cerebellar ataxia associated with subclinical celiac disease responding to gluten-free diet", Neurology 1999 Oct 22;53(7):1606-8 Page 15 of 399

Pellecchia MT, Scala R, Filla A, De Michele G, Ciacci C, Barone P., "Idiopathic cerebellar ataxia associated with celiac disease: lack of distinctive neurological features", J Neurol Neurosurg Psychiatry 1999 Jan;66(1):32-5

Dipartimento di Scienze Neurologiche, Sistematica-Universita di Napoli Federico II, Italy.

OBJECTIVES: To determine the occurrence of celiac disease in a population of ataxic patients without definite diagnosis and to characterise distinctive features which may help to differentiate cerebellar ataxia with and without celiac disease. METHODS: Twenty four ataxic patients without definite diagnosis (group A) and 23 ataxic patients with definite diagnosis (group B) were screened for antigliadin (AGAs) and antiendomysium antibodies (EMAs). Patients with a positive AGA or EMA test underwent endoscopic biopsy of the duodenal mucosa. RESULTS: There was an increased prevalence of celiac disease in group A (3/24) compared with group B (0/23). None of the celiac patients presented gastrointestinal symptoms or malabsorption signs. None of the ataxic patients with celiac disease had early onset ataxia. CONCLUSIONS: Celiac disease is associated with ataxic syndromes without definite diagnosis, suggesting that it plays a part in the pathogenesis of some ataxic syndromes. The absence of distinctive neurological features in ataxic patients with celiac disease suggests that a

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search should be made for celiac disease markers in all ataxic patients without definite diagnosis.

Finelli PF., McEntee WJ., Ambler M., Kestenbaum D., "Adult celiac disease presenting as cerebellar syndrome", Neurology, Vol 30, Issue 3 245-249

A progressive pancerebellar syndrome in a 57-year-old man heralded what was subsequently diagnosed by malabsorption studies and jejunal biopsy as adult celiac disease. Postmortem examination demonstrated characteristic gastrointestinal and cerebral abnormalities associated with this enteropathy. The neuropathology underlying the ataxia, as well as the clinical features of palatal myoclonus and marked speech impairment, included marked cerebellar cortical atrophy with cell loss in dentate and olivary nuclei. Intestinal-absorption studies are indicated to evaluate patients with any neurologic illness that may be related to malabsorption.

This article has been cited by other articles:

Tijssen, M. A. J., Thom, M., Ellison, D. W., Wilkins, P., Barnes, D., Thompson, P. D., Brown, P. (2000). Cortical myoclonus and cerebellar pathology. Neurology 54: 1350-1356 [Abstract] [Full Text]

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Kaplan JG:, Pack D., Horoupian D., DeSouza T, M Brin, Schaumburg H, "Distal axonopathy associated with chronic gluten enteropathy: a treatable disorder", Neurology, Vol 38, Issue 4 642645

ABSTRACT (Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461) Our experience with one patient and literature review reveals that patients with chronic gluten enteropathy and severe steatorrhea may develop a generalized peripheral neuropathy of the distal axonopathy type. Vitamin levels are usually normal, and the neuropathy appears to respond to gluten restriction.

Kepes JJ., Chou SM., Price LW. Jr, "Progressive multifocal leukoencephalopathy with 10-year survival in a patient with nontropical sprue. Report of a case with unusual light and electron microscopic features", Neurology, Vol 25, Issue 11 1006-1012

A 46-year-old man with nontropical sprue had anemia and hypoproteinemia for several years, until his condition was diagnosed and treated with dietary measures. Within a year after the diagnosis, progressive multifocal leukoencephalopathy developed, and the patient had a slightly fluctuating chronic downhill course until he died 10 years later. It is postulated that this patient's immune deficiency was related to his malabsorption syndrome and hypoglobulinemia, and the course became unusually protracted (longest reported course in the American literature) because of restoration of Page 18 of 399

plasma protein levels. Autopsy showed the classic findings of progressive multifocal leukoencephalopathy, with much tissue loss of subcortical white matter and active perivascular inflammatory foci with numerous eosinophilic granulocytes. On electron microscopy, oligodendrocyte nuclei and cytoplasm were crowded with virions, but many myelin sheaths invested by severely infected oligodendrocytic processes were remarkably well preserved. This fact would argue against a direct cause-and-effect relationship between infection of oligodendrocytes and myelin breakdown in progressive multifocal leukoencephalopathy. The likelihood of an autoimmune mechanism at work in this disease is suggested, and the role of eosinophils and other cells in such process is considered.

This article has been cited by other articles:

Hadjivassiliou, M, Chattopadhyay, A K, Davies-Jones, G A B, Gibson, A, Grünewald, R A, Lobo, A J (1997). Neuromuscular disorder as a presenting feature of coeliac disease. J. Neurol. Neurosurg. Psychiatry 63: 770-775 [Abstract] [Full Text]

Ward ME., Murphy JT., Greenberg GR., "Celiac disease and spinocerebellar degeneration with normal vitamin E status", Neurology, Vol 35, Issue 8 1199-1201

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We studied a 47-year-old man with spinocerebellar degeneration and malabsorption due to celiac enteropathy; the serum vitamin E level was normal. The neurologic disorder initially deteriorated despite improvement of small bowel histology on a gluten-free diet and vitamin E therapy, but later stabilized. The etiology of the neurologic disorder in adult celiac disease has not been identified and does not appear to be vitamin E deficiency.

This article has been cited by other articles:

Pellecchia, M. T., Scala, R., Perretti, A., De Michele, G., Santoro, L., Filla, A., Ciacci, C., Barone, P. (1999). Cerebellar ataxia associated with subclinical celiac disease responding to gluten-free diet. Neurology 53: 1606-1606 [Full Text]

Perkin, G D, Murray-Lyon, I (1998). Neurology and the gastrointestinal system. J. Neurol. Neurosurg. Psychiatry 65: 291-300 [Full Text]

Mauro A, Orsi L, Mortara P, Costa P, Schiffer D Cerebellar syndrome in adult celiac disease with vitamin E deficiency. Acta Neurol Scand 1991 Aug;84(2):167-70 Neurological Clinic II, University of Turin, Italy. We studied a woman with adult onset celiac disease complicated by a Page 20 of 399

cerebellar syndrome that progressed despite the resolution of the malabsorption symptoms with a gluten free diet. The patient presented vitamin E deficiency and the cerebellar symptoms improved with vitamin E therapy. This case supports the possible role of this deficiency in the development of the neurological complications of celiac disease.

Bhatia KP, Brown P, Gregory R, Lennox GG, Manji G., Thompson PD., Ellison PD., Marsden CD., "Progressive myoclonic ataxia associated with coeliac disease. The myoclonus is of cortical origin, but the pathology is in the cerebellum", Brain, Vol 118, Issue 5 1087-1093

ABSTRACT (University Department of Clinical Neurology, Institute of Neurology, London, UK). We report four patients with a progressive myoclonic ataxic syndrome and associated coeliac disease. The onset of the neurological syndrome followed the gastrointestinal and other manifestations of coeliac disease while on a gluten-free diet, in the absence of overt features of malabsorption or nutritional deficiency. The condition progressed despite strict adherence to diet. The neurological syndrome was dominated by action and stimulus sensitive myoclonus of cortical origin with mild ataxia and infrequent seizures. Plasmapharesis and immunosuppressive treatment were tried in two patients but were not beneficial. Post-mortem examination of the brain in one case showed selective symmetrical atrophy of the cerebellar hemispheres with Purkinje cell loss and Page 21 of 399

Bergmann astrocytosis, and with preservation of the cerebral hemispheres and brainstem. Coeliac disease should be considered in the differential diagnosis of all patients presenting with a progressive myoclonic ataxic syndrome.

This article has been cited by other articles:

Bürk, K., Bösch, S., Müller, C. A., Melms, A., Zühlke, C., Stern, M., Besenthal, I., Skalej, M., Ruck, P., Ferber, S., Klockgether, T., Dichgans, J. (2001). Sporadic cerebellar ataxia associated with gluten sensitivity. Brain 124: 1013-1019 [Abstract] [Full Text]

SMITH, G D P, SALDANHA, G, BRITTON, T C, BROWN, P (1997). Neurological manifestations of coeliac disease. J. Neurol. Neurosurg. Psychiatry 63: 550-551 [Full Text]

P Collin, T Pirttila, T Nurmikko, H Somer, T Erila and O Keyrilainen, "Celiac disease, brain atrophy, and dementia", Neurology, Vol 41, Issue 3 372-375 ABSTRACT (Department of Internal Medicine, Tampere University Central Hospital, Finland. We report 5 patients who developed dementia before age 60 and were subsequently found to have celiac disease (CD). Intellectual deterioration ranged from moderate to severe, and diffuse cerebral or cerebellar atrophy was found on brain CT. Diagnosis of CD was confirmed by findings of subtotal villous atrophy in jejunal biopsy specimens and positive serum reticulin and gliadin antibodies. Page 22 of 399

Conspicuously, gastrointestinal symptoms were mild. The gluten-free diet failed to improve the neurologic disability except in 1 patient. CD is a multisystem disorder and may play a role in some cases of presenile dementia. Although the pathogenetic mechanisms are obscure, immunologic mechanisms are implicated.

This article has been cited by other articles:

Hadjivassiliou, M, Chattopadhyay, A K, Davies-Jones, G A B, Gibson, A, Grünewald, R A, Lobo, A J (1997). Neuromuscular disorder as a presenting feature of coeliac disease. J. Neurol. Neurosurg. Psychiatry 63: 770-775 [Abstract] [Full Text]

"Sporadic cerebellar ataxia associated with gluten sensitivity", Brain, Vol. 124, No. 5, 1013-1019, May 2001

K. Bürk1, S. Bösch1, C. A. Müller2, A. Melms1, C. Zühlke3, M. Stern4, I. Besenthal5, M. Skalej6, P. Ruck7, S. Ferber1, T. Klockgether8 and J. Dichgans1 Department of Neurology, University of Tübingen,

A total of 104 patients with sporadic cerebellar ataxia were tested for antigliadin and antiendomysium antibodies. Twelve individuals (11.5%) with gluten sensitivity underwent duodenal biopsy and extensive clinical, electrophysiological, neuropsychological, radiological and laboratory Page 23 of 399

investigations including human leucocyte antigen (HLA) typing. Two patients showed typical changes of gluten-sensitive enteropathy with crypt hyperplasia and mucosal flattening. In five patients, the intraepithelial lymphocyte count was elevated. Sporadic ataxia with gluten sensitivity was found to be tightly linked to the HLA DQB1*0201 haplotype (70%). Neurological symptoms were not related to hypovitaminosis or inflammatory CSF changes. The clinical syndrome was dominated by progressive cerebellar ataxia with ataxia of stance and gait (100%), dysarthria (100%) and limb ataxia (97%). Oculomotor abnormalities were gaze-evoked nystagmus (66.7%), spontaneous nystagmus (33.3%), saccade slowing (25%) and upward gaze palsy (16.7%). Extracerebellar features also included deep sensory loss (58.3%), bladder dysfunction (33.3%) and reduced ankle reflexes (33.3%). In accordance with clinical findings, electrophysiological investigations revealed prominent axonal neuropathy with reduced amplitudes (50%) and abnormal evoked potentials (58.3%). On neuropsychological testing, patients presented with moderate verbal memory and executive dysfunction. All patients had evidence of cerebellar atrophy on MRI. We conclude that sporadic ataxia may be associated with positive antibodies against gliadin. Nevertheless, mucosal pathology does not represent an obligatory condition of ataxia with gluten sensitivity. The fact that the disease is strongly associated with the same HLA haplotypes found in coeliac disease not only demonstrates coeliac disease and ataxia with gluten sensitivity to be part of the same disease entity but supports the hypothesis of an immunological pathogenesis of cerebellar degeneration.

RA Hermaszewski, S Rigby and AG Dalgleish, "Coeliac disease presenting with cerebellar degeneration", Postgraduate Medical Journal, 1991, Vol 67, 1023-1024 Page 24 of 399

ABSTRACT (Northwick Park Hospital and Clinical Research Centre, Harrow, UK) A case of rapidly progressive cerebellar degeneration with bilateral sixth nerve palsies is described in whom investigation revealed the presence of unsuspected coeliac disease. In spite of treatment with a gluten free diet, rapid fatal deterioration occurred. Coeliac disease should be considered in patients with encephalopathy of obscure origin.

"Headache and CNS white matter abnormalities associated with gluten sensitivity", Neurology 2001;56:385-388 M. Hadjivassiliou, MD;, R.A. Grünewald, DPhil;, M. Lawden, MD;, G.A.B. Davies–Jones, MD;, T. Powell, FRCP; and C.M.L. Smith, FRCPath From the Departments of Clinical Neurology (Drs. Hadjivassiliou, Grünewald, and Davies– Jones) and Neuroradiology and Neuropathology (Drs. Powell and Smith), The Royal Hallamshire Hospital, Sheffield; and Department of Clinical Neurology (Dr. Lawden), Leicester Royal Infirmary, Leicester, UK.

Address correspondence and reprint requests to Dr. M. Hadjivassiliou, Consultant Neurologist, Department of Clinical Neurology, The Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF UK; email: [email protected]

The authors describe 10 patients with gluten sensitivity and abnormal MRI. All experienced episodic Page 25 of 399

headache, six had unsteadiness, and four had gait ataxia. MRI abnormalities varied from confluent areas of high signal throughout the white matter to foci of high signal scattered in both hemispheres. Symptomatic response to gluten-free diet was seen in nine patients.

Chinnery PF., Reading PJ., Milne D., Gardner-Medwin D., Turnbull DM., "CSF antigliadin antibodies and the Ramsay Hunt syndrome", Neurology, Vol 49, Issue 4 1131-1133 ABSTRACT (Department of Neurology, The Royal Victoria Infirmary, Newcastle upon Tyne, U.K.) Although the association between celiac disease and progressive myoclonic ataxia is well recognized, in each of the reported cases the neurologic features began in middle adult life and usually in patients who had clinical or laboratory evidence of malabsorption. We report a case of progressive myoclonic ataxia and epilepsy (Ramsay Hunt syndrome) that began in childhood. In this patient there were no features suggestive of gluten intolerance. The presence of antigliadin antibodies in the serum and CSF suggested celiac disease was the cause of the patient's neurologic syndrome. Duodenal morphologic abnormalities reversed with treatment but no major changes were noted in the patient. Celiac disease should be considered in the differential diagnosis of myoclonic ataxia at any age, even in the absence of clinical evidence of gluten-sensitive enteropathy.

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Tijssen MA, Ellison DW, Barnes D., Thompson PD., Brown P., "Cortical myoclonus and cerebellar pathology", Neurology 2000;54:1350-1356 Department of Neurology, University of Amsterdam, PO Box 22660, 1100 DD Amsterdam, The Netherlands. OBJECTIVE: To study the electrophysiologic and pathologic findings in three patients with cortical myoclonus. In two patients the myoclonic ataxic syndrome was associated with proven celiac disease. BACKGROUND: The pathologic findings in conditions associated with cortical myoclonus commonly involve the cerebellar system, but there has only been one report of cerebellar pathology in a patient in whom cortical myoclonus was physiologically characterized antemortem. METHODS: Cortical somatosensory evoked potentials (SEPs) were recorded and EEG activity was averaged preceding myoclonic electromyographic activity. In one patient cortico-cortical inhibition was tested using two paired ipsilateral magnetic stimuli over the motor strip. Neuropathologic examination was carried out, including linear Purkinje cell densities/millimeter calculations for different regions of the cerebellum. RESULTS: The electrophysiology showed evidence of dysfunction of the sensorimotor cortex with enlarged SEPs and a time-locked cortical potential preceding the action myoclonus. In addition, motor cortical inhibition was abnormal in one case. Pathology showed unremarkable primary sensory, motor, and premotor cerebral cortices, except for unilateral gliosis of the motor cortex in one case. The cerebellum showed patchy atrophy and ongoing degeneration. A striking feature was the greater severity of Purkinje cell loss and Bergmann gliosis in the outer aspects than in the depths of the folia. CONCLUSIONS: Pathologic abnormalities are paradoxically mainly located in the cerebellum in Page 27 of 399

some patients with cortical myoclonus, despite clear electrophysiologic evidence of cortical dysfunction. This observation suggests that enhanced excitability of the sensorimotor cortex may arise as a distant effect of cerebellar pathology.

Harding AE, Muller DP, Thomas PK, Willison HJ., "Spinocerebellar degeneration secondary to chronic intestinal malabsorption: a vitamin E deficiency syndrome", Ann Neurol 1982 Nov;12(5):419-24

Two adults are described who developed a progressive neurological disorder more than 20 years after the onset of chronic fat malabsorption. The clinical features included dysarthria, cerebellar ataxia, and prominent proprioceptive loss with depressed or absent tendon reflexes. Serum vitamin E was undetectable in both cases. One patient improved clinically and electrophysiologically after oral therapy with vitamin E. The findings in these patients were similar to those in others recently reported with vitamin E deficiency associated with biliary atresia. Electrophysiological observations suggested that the human deficiency state parallels that found neuropathologically in vitamin Edeficient animals.

Dickey W., "Epilepsy, cerebral calcifications, and coeliac disease", Lancet 1994 Dec 10;344(8937):1585-6 Page 28 of 399

atopics

Zauli D, Grassi A, Granito A, Foderaro S, De Franceschi L, Ballardini G, Bianchi FB, Volta U., "Prevalence of silent coeliac disease in atopics", Dig Liver Dis 2000 Dec;32(9):775-9

Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, Italy. [email protected]

BACKGROUND: Coeliac disease sometimes runs a subclinical/silent course and is often associated with immunologic and nonimmunologic diseases. Although atopy is described as one of the most frequently associated conditions, the prevalence of coeliac disease in atopics has not yet been established. AIM: To evaluate the frequency of coeliac disease in an Italian series of atopics. PATIENTS AND METHODS: Sera from 401 consecutive atopics with no clinical evidence of malabsorption were tested for IgA antiendomysial antibodies by indirect immunofluorescence on human umbilical cord and IgA anti tissue transglutaminase by enzyme-linked immunosorbent assay Results. Four patients (1%) were Page 29 of 399

found to be positive for both autoantibodies. Intestinal biopsy confirmed the diagnosis of active coeliac disease. One of the 4 coeliacs was also affected by Down's syndrome, autoimmune thyroiditis and coeliac hepatitis. In another case, a previously unknown severe iron deficiency was detected. CONCLUSIONS: The present study shows, for the first time, that the prevalence of coeliac disease in atopics is 1%, which is significantly higher than that in the general Italian population. Therefore, atopy should be considered a condition at risk and atopic patients routinely screened by means of specific autoantibody testing.

Evitare glutine e caseina nell’autismo: i riscontri scientifici

O’Banion nel 1978 aveva monitorato il comportamento e l’alimentazione di un bambino autistico di otto anni. Ne risultò che il frumento e derivati, lo zucchero, il latte e i latticini causavano nel bambino dei disturbi comportamentali. In particolare, l’intolleranza a glutine e caseina acuiva i comportamenti anomali dei bambini autistici, fra cui "l’iperattività, il riso forzato, nonché le azioni compulsive e incontrollate". Page 30 of 399

O'Banion D, Armstrong B, Cummings RA, Stange J, "Disruptive behavior: a dietary approach", J. Autism 8 (1978), p325-307

Nel 1981 Reichelt scoprì per la prima volta, dalle analisi delle urine, elevati livelli di alcuni peptidi opioidi (derivanti dal malassorbimento di glutine e caseina) nel 70-80% degli autistici. Nel 1988 Gillberg mostrò che questi peptidi opioidi erano presenti nel fluido cerebrospinale dei bambini autistici. Tra il 1986 e il 1991 Reichelt riportò casi di guarigione o di forti miglioramenti tra i bambini autistici trattati con diete senza glutine e senza caseina.

Reichelt K, The Journal of Applied Nutrition, volume 42, no. 1, 1990 ABSTRACT: Sulla base dei complessi profili urinari di peptidi da glicoproteine, 19 bambini con sindromi autistiche sono stati trattati con regimi alimentari completamente senza glutine e caseina oppure parzialmente. Prima di tale intervento 5 dei 15 pazienti soggetti a completa valutazione avevano elevati livelli di anticorpi al glutine o alla caseina. Abbiamo dimostrato una diminuzione dei livelli di peptidi urinari a seguito di tale regime alimentare. Fu riscontrato un miglioramento nei comportamenti e l’attività epilettica diminuì.

Reichelt LL, Lind G, Nodland M, "Probable Etiology and Possible Treatment of Childhood Autism", Brain Dysfunction, 4 (6) 308-319 (1991)

Gillberg C. (1988) "The role of endogenous opioids in autism and possible relationships to clinical features" in Wing, L. (ed.) Aspects of Autism: Biological Research. Gaskell:London, pp. 31-37.

Gillberg C, “Endogenous opioids and opiate antagonists in autism: brief Page 31 of 399

review of empirical findings and implications for clinicians”, Dev Med Child Neurol. 1995 Mar;37(3):239-45.

Frammenti di proteine derivanti da cibo malassorbito hanno come effetto quello di scatenare le manifestazioni tipiche dell’autismo in animali di laboratorio [Panksepp, 1979; Gillman, 1986] ed è stato mostrato che hanno un’azione opioide [Ozonoff, 1994].

Panksepp, J. (1979) "A neurochemical theory of autism." Trends in Neuroscience, 2: 174-177

Sahley TL, Panksepp J, “Brain opioids and autism: an updated analysis of possible linkages”, J Autism Dev Disord 1987 Jun; 17(2):201-16. “Una rassegna della letteratura sull’autismo mostra che questo deriva, almeno in parte da interferenze opioidi nel cervello. Ciò è confermato anche da studi su animali. Tali sostanze opioidi modulano i processi socio-emotivi, e la possibilità di bloccare l’attività opioide nel cervello può essere terapeutica per l’autismo infantile”.

Sandyk R, Gillman MA, “Infantile autism: a dysfunction of the opioids?”, Med Hypotheses 1986 Jan; 19(1):41-5 “Postuliamo che l’autismo infantile può essere causato da una disfunzione del sistema endogeno opioide. Discutiamo le evidneze che correlano le caratteristche di questa condizione con la disfunzione opiatergica.

Shattock (1998) ha esaminato in 10 anni i profili urinari di circa 1500 autistici. La concentrazione e il tipo di peptidi esogeni riscontrati nelle loro urine Page 32 of 399

variavano in maniera prevedibile a secondo del tipo e gravità della sintomatologia. Persone sane facevano da riferimento di controllo ed erano caratterizzate dall'assenza nelle urine di questi peptidi opioidi. L'attività opioide causata da concentrazioni anomale di peptidi andrebbero a disturbare a vari livelli una serie di funzioni del sistema nervoso centrale: percezione, apprendimento, emozioni, stati d'animo e comportamento.

Shattock P, Kennedy A, Rowell F, Berney T, "Role of Neuropeptides in Autism and their relationship with Classical Neurotransmitters", (1990) Brain Dysfunction 3: 328-345

Williams K, Shattock P, Berney T, "Proteins, Peptides and Autism: Part 1. Urinary Protein Patterns in Autism as revealed by Sodium Dodecyl Sulphate-Polyacrylamide Gel Electrophoresis and Silver Staining", (1991) Brain Dysfunction 4:320-322

Shattock P, Lowdon G, "Proteins, Peptides and Autism: Part 2. Implications for the Education and Care of People with Autism", (1991) Brain Dysfunction 4:323-334

Mills MJ, Savery D, Shattock P, "Rapid Analysis of low levels of indolyl-3acryloylglycine in human urine by high-performance liquid chromatography" (1998) Journal of Chromatography B 712:51-58

Shattock P, Savery D, Whiteley P, "Autism as a metabolic disorder / Guidelines for the implementation of a gluten and/or casein free diet with people with autism or associated spectrum disorders", Autism Research Unit, 1998

Whiteley P, Rodgers J, Shattock P, "Clinical features associated with autism: Observations of symptoms outside the diagnostic boundaries of Page 33 of 399

autistic spectrum disorders" (1998) Autism 2: 415-422

Knivsberg, Cade e Risebro aggiungono il loro lavoro a quello di Reichell, Freeidman e Shattock, e confermano che bambini autistici migliorano enormemente se si interviene con un regime alimentare dal quale vengano rimossi caseina e glutine.

Knivsberg A-M et al. (1990) "Dietary intervention in autistic syndromes," Brain Dysfunction, 3:315- 27.

Cade R, "Autismo e schizofrenia: disfunzioni intestinali", Nutritional Neuroscience, in press 1999 Abstract: "Una dieta senza glutine e caseina ha portato ad un miglioramento entro 3 mesi nell'81% dei bambini autistici. I nostri dati supportano la teoria secondo la quale schizofrenia ed autismo sono dovuti all'assorbimento di esorfine formate nell'intestino dalla digestione di glutine e caseina".

Risebro B, “Gluten-free diet in infantile autism”, Tidsskr Nor Laegeforen 1991 Jun 10;111(15):1885-6

Lensing mostrò che usando il farmaco antagonista dell’attività opioide, naltrexone, si ottenevano miglioramenti nel comportamento e capacità di 2 bambini autistici. Le conclusioni da trarsi da questo trial clinico sono che l’avversione al contatto visivo e l’isolamento nei bambini autistici può essere causato da eccessiva attività opioide che interferisce con i processi corticotalamocorticali, particolarmente rilevanti per gli stimoli visivi. Page 34 of 399

Lensing P, Schimke H, Klimesch W, Pap V, Szemes G, Klingler D, Panksepp J, “Clinical case report: opiate antagonist and event-related desynchronization in 2 autistic boys”, Neuropsychobiology 1995;31(1):16-23

A supporto della teoria opioide, Alan Friedman, ricercatore della Johnson & Johnson, nei primi anni ’90 ha trovato un composto molto tossico nelle urine di bambini autistici, la demorfina, un peptide ad attività opioide (10 milioni di volte più potente e tossica della morfina). La demorfina è stata trovata solo un'altra volta in natura e cioè nel veleno della rana freccia ("dart frog") dell'Amazzonia! Ulteriori ricerche confermarono che tale opioide compare sempre in bambini autistici che ingeriscono anche minuscole quantità di caseina o glutine.

Pedersen, a sua volta, nel 1999 trovò elevati livelli di un tripeptide complesso nelle urine del 60% dei pazienti autistici. Questo peptide stimolava siti opioidi attivati dalla serotonina. Tale peptide era assente nelle urine di pazienti di controllo sani.

Pedersen OS, Liu Y, “Serotonin uptake stimulating peptide found in plasma of normal individuals and in some autistic urines”, J Pept Res 1999 Jun;53(6):641-6 ABSTRACT: Abbiamo isolato nel plasma e nelle urine di pazienti autistici un tripeptide che stimola l’utilizzo di serotonina (5-HT) nelle piastrine. Questo peptide è stato purificato mediante HPLC e caratterizzato da sequenzializzazione e spettroscopia di massa. Circa il 60% dei bambini autistici (diagnosi effettuata sulla base del DSM III-R) avevano un consistente picco cromatografico HPLC derivante dalla presenza di questo peptide nelle urine, mentre lo stesso non era presente nei bambini di controllo. Page 35 of 399

Lucarelli (1995), dell’università “La Sapienza” di Roma, trovò elevati livelli di anticorpi IgA e IgG alla caseina in pazienti autistici. A seguito di un periodo di 8 settimane in cui venivano rimossi i cibi allergenici fu registrato un notevole miglioramento nei sintomi comportamentali.

Lucarelli S, Frediani T, Zingoni AM, Ferruzzi F, Giardini O, Quintieri F, Barbato M, D'Eufemia P, Cardi E, “Food allergy and infantile autism”, Panminerva Med 1995 Sep;37(3):137-41

ABSTRACT (Dipartimento di Pediatria, Università "La Sapienza", Roma): La eziopatogenesi dell'autismo infantile è ancora ignota. Recentemente alcuni autori hanno suggerito che peptidi di origine alimentare possono essere capaci di determinare effetti tossici a livello di sistema nervoso centrale interagendo con neurotrasmettitori. Infatti un peggioramento dei sintomi neurologici è stato riportato in pazienti autistici a seguito del consumo di latte e grano. Scopo di questo studio è stato di verificare l'efficacia di un'alimentazione senza latte di mucca (o altre sostanze negli alimenti che avevano dato una reazione positiva allergica al patch test) in 36 pazienti autistici. Abbiamo anche esaminato riscontri immunologici di allergie alimentari nei pazienti autistici che non avevano alcuna restrizione del cibo utilizzato. Abbiamo notato un notevole miglioramento nei sintomi comportamentali di pazienti dopo un periodo di 8 settimane che seguivano una dieta selezionata antiallergenica ed abbiamo riscontrato elevati livelli di anticorpi specifici IgA verso caseina, lattoalbumina e beta-lattoglobulina e IgG e IgM per la caseina. I livelli di questi anticorpi erano significativamente più elevati di quelli di un gruppo di controllo che consisteva di 20 bambini sani. I nostri risultati ci portano ad ipotizzare una correlazione tra allergia al cibo ed autismo infantile come del resto è già stato suggerito in base ad altri disturbi del sistema nervoso centrale (teoria opioide).

Page 36 of 399

Uhlig (1997) monitorò l’attività elettrica cerebrale in bambini con sindrome di deficit attentivo ed iperattività. Egli dimostrò per la prima volta una correlazione tra attività elettrica cerebrale ed assunzione di cibi glutine e caseina, la cui sospensione dalla dieta faceva scomparire anche i sintomi mentali e comportamentali.

Uhlig T, Merkenschlager A, Brandmaier R, Egger J, "Mappatura topografica dell'attività elettrica cerebrale in bambini con sindrome di deficit attentivo ed iperattività indotta da cibo", Eur J Pediatr, luglio 1997; 156(7):557-61

ABSTRACT (Institute for Child Health Research, Clinical Sciences Division, West Perth, Australia): In 15 bambini colpiti da sindrome di deficit attentivo ed iperattività è stata effettuata la mappatura topografica EEG dell'attività elettrica del cervello monitorando l'effetto che aveva il somministrare o l'evitare alcuni cibi in questione. Durante il consumo dei cibi sensibilizzanti ci fu un aumento notevole di attività betale nelle aree frontotemporali del cervello. L'indagine è la prima a dimostrare una correlazione tra attività elettrica del cervello ed assunzione di cibi sensibilizzanti in bambini con sindrome di deficit attentivo indotto ed iperattività indotto da cibo. CONCLUSIONI: Questi risultati sono consistenti con l'ipotesi che in sottogruppi di bambini con sindrome di deficit attentivo ed ipersensibilità alcuni cibi possono influenzare non solo i sintomi ma anche alterare l'attività elettrica del cervello.

A conferma della teoria opioide, D’Eufemia e collaboratori trovarono una permeabilità intestinale alterata nel 43% di 21 bambini autistici, ma in nessuno dei bambini di controllo. Page 37 of 399

D'Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M, Cardi E, Giardini O, “Abnormal intestinal permeability in children with autism”, Acta Paediatr 1996 Sep; 85(9):1076-9

ABSTRACT (Institute of Pediatrics, La Sapienza University of Rome, Italy) Abbiamo determinato l’incidenza di danno alla mucosa intestinale usando il test di permeabilità intestinale in 21 bambini autistici che non avevano nessun riscontro clinico o di laboratorio relativamente a note patologie intestinali. È stata accertata permeabilità instestinale alterata in 9 dei 21 (43%) pazienti autistici, ma in nessuno dei 40 bambini di controllo. Confrontati con il gruppo di controllo, questi nove pazienti mostravano un simile recupero medio da mannitolo, ma un recupero da lattulosio medio significativamente più elevato (1.64% +/- 1.43 vs 0.38% +/- 0.14; P < 0.001). Speculiamo che un’alterata permeabilità intestinale potrebbe rappresentare un possibile meccanismo per l’aumento del passaggio attraverso la mucosa intestinale di peptidi derivati da cibo con conseguenti anomalie conmportamentali.

Pelliccia e collaboratori esaminarono con elettroencefalografia 3 bambini con problemi comportamentali soggetti a crisi epilettiche. “Invece di usare agenti anticonvulsivi il trattamento si basò sulla rimozione del latte e derivati dalla dieta”. Un miglioramento fu osservato nel comportamento dei bambini e le anomalie elettroencefaliche relative all’attività epilettica scomparvero.

Pelliccia A, Lucarelli S, Frediani T, D'Ambrini G, Cerminara C, Barbato M, Vagnucci B, Cardi E, “Partial cryptogenetic epilepsy and food allergy/intolerance. A causal or a chance relationship? Reflections on three clinical cases”, Minerva Pediatr 1999 May; 51(5):153-7 Page 38 of 399

ABSTRACT (Neurological and Psychiatric Sciences Department, University of Rome, La Sapienza) La possibilità che alcuni cibi o allergeni possano indurre convulsioni è stata già riportata nella letteratura. Nessuno di questi studi ha, comunque, mostrato una correlazione tra allergia alimentare ed epilessia, essendo stata la maggior parte dei rapporti anedottali ed aperti a varie ipotesi eziologiche. Questo studio riguarda 3 bambini con epilessia criptogenetica parziale, diagnosticata per mezzo di elettroencefalografia, e con disturbi comportamentali (iperattività, disturbi del sonno e problemi nello scrivere). In questi pazienti, invece di usare agenti anticonvulsivi, il trattamento si è basato su un regime alimentare senza latte e derivati, lavorando sull’ipotesi che ci potesse essere una relazione casuale tra intolleranza a questo tipo di alimento e i sintomi epilettici. Fu osservato un miglioramento nel comportamento dei bambini e, inoltre, le anomalie elettro-encefalografiche scomparvero. In test a doppio cieco con controllo placebo, la provocazione con latte non provocava una reazione immediata ma solo dopo alcuni giorni. Iniziare di nuovo il regime controllato, in tutti i casi, portava alla scomparsa delle alterazioni dell’elettroencefalogramma. In conclusione, sembra giustificato ipotizzare il ruolo di intolleranze alimentari nella comparsa di crisi epilettiche convulsive, almeno quelle nella forma criptogenetica parziale.

In conclusione è necessario sottolineare la differenza tra allergia alimentare e intolleranza alimentare. Anche in assenza di anticorpi specifici per un cibo, cioè un’allergia, ciò non esclude che l’organismo sia diventato intollerante al cibo, di solito dopo un prolungato periodo in cui non riesce più a smantellarlo normalmente. I frammenti di cibo malassorbiti possono andare a sovraccaricare il sistema endocrino, neurologico o altri.

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B12 deficiency in gluten catastrophe

Am J Gastroenterol 2001 Mar;96(3):745-50 Vitamin B12 deficiency in untreated celiac disease. Dahele A, Ghosh S.

Department of Medical Sciences, University of Edinburgh, Western General Hospital, Scotland.

OBJECTIVES: Iron and folate malabsorption are common in untreated celiac disease as the proximal small intestine is predominantly affected. Vitamin B12 deficiency is thought to be uncommon, as the terminal ileum is relatively spared. This study aims to investigate the prevalence of vitamin B12, deficiency in patients with untreated celiac disease. METHODS: Prospective study of 39 consecutive biopsy-proven celiac disease patients (32 women, seven men; median age 48 yr, range 22-77 yr) between September 1997 and February 1999. The full blood count, serum vitamin B12, red blood cell folate, and celiac autoantibodies (IgA antigliadin and IgA antiendomysium antibodies) were measured before and after a median of 4 months (range 2-13 months) of treatment with a gluten-free diet. In vitamin B12-deficient patients, intrinsic factor antibodies and a Schilling test, part 1, were performed. RESULTS: A total of 16 (41%) patients were vitamin B12 deficient (60% of amylase activity was consistent with the presence of MA. Immunoglobulin G (IgG) and immunoglobulin A (IgA) circulating autoantibodies to amylase were measured using recently developed enzyme-linked immunosorbent assay (ELISA), using porcine amylase as antigen. Results were expressed as arbitrary units (AUs). Statistical analysis was performed by Student's t test for unpaired data. IgA and IgG antibodies to exocrine pancreas tissue were detected by indirect immunofluorescence on human pancreas cryosections. RESULTS: Serum immunoprecipitation with either protein A Sepharose or polyethylene glycol reduced amylase activity from 1698 to 89 U/L (94.8%) and to 75 U/L (95.6%), with only marginal reduction in control serum samples. The ELISA for autoantibodies to amylase detected high values, both IgA (3531 AU) and IgG (1855 AU), in the serum sample from the patient at CD diagnosis. IgA autoantibodies (mean +/- standard deviation) were 3.4 +/- 2.5 AU in healthy controls, and 2.1 +/- 1.2 AU in celiac controls; IgG autoantibodies were 10 +/- 4.8 AU in healthy controls and 8.5 +/- 3.2 AU, respectively. Autoantibodies to exocrine pancreas tissue were documented in patient sera at the time of CD diagnosis, both IgA and IgG, but not in control groups. Preincubation of patient's serum with excess of alpha-amylase specifically inhibited antibody binding to coated amylase in Page 287 of 399

the ELISA, and partially inhibited immunoreactivity to exocrine pancreas. Autoantibodies to alpha-amylase and to exocrine pancreas declined in CD patients after institution of a gluten-free diet. CONCLUSIONS: Few cases of MA have been described in children, and in all amylase determination was part of the clinical investigation for abdominal pain or trauma. (ABSTRACT TRUNCATED)

Collin P, Salmi J, Hallstrom O, Reunala T, Pasternack A., "Autoimmune thyroid disorders and coeliac disease", Eur J Endocrinol 1994 Feb;130(2):137-40

Department of Clinical Sciences, University of Tampere, Finland.

Eighty-three patients with autoimmune thyroid disorders were screened for coeliac disease. The screening was performed with IgA-class reticulin and endomysium antibody, IgA- and IgG-class gliadin antibody tests, and various biochemical tests for malabsorption. None of the tested subjects had selective IgA deficiency, which excludes the possibility of not detecting positives by an IgA-class test. Of the 83 patients, three asymptomatic coeliac patients were found, and one patient with coeliac disease previously diagnosed, an overall frequency of 4.8%. In addition, 25 patients with a solitary nodule of the thyroid gland were examined and one of them (4%) was found to have coeliac disease. By contrast, one (0.4%) out of 249 age- and sex-matched blood Page 288 of 399

donors was found to have coeliac disease. All newly detected coeliac patients had IgA-class gliadin, reticulin and endomysium antibodies, but none of the patients had any gastrointestinal symptoms or abnormal biochemical findings suggesting coeliac disease. Treatment of thyroid disorders and coeliac disease was successful in these patients. The present results confirm that the frequency of subclinical coeliac disease is increased among patients with autoimmune thyroid disorders. IgA-class reticulin, endomysium or gliadin antibody tests are suitable screening methods for detecting these patients, as far as selective IgA-deficiency is excluded.

Counsell CE, Ruddell WS., “Association between coeliac disease and autoimmune thyroid disease”, Gut. 1995 Mar;36(3):475-6.

Counsell, et al., "Coeliac disease and autoimmune thyroid disease", Gut, 1994, June, Vol 35, Pg. 844-6.

A well defined cohort of coeliac patients was studied prospectively to assess the prevalence of coexisting thyroid disease and positive thyroid autoantibodies. Comparison with epidemiological data on the prevalence of coeliac disease in a neighboring area suggested that few adult coeliac patients had been missed. Overall, 14% of the coeliac patients had thyroid disease: 10.3% were hypothyroid and 3.7% hyperthyroid, both significantly more than expected. There were significantly more coeliac disease patients with thyroid autoantibodies than expected--11% had thyroglobulin antibodies Page 289 of 399

and 15% had thyroid microsomal antibodies. This association is clinically important. Three patients are described in whom the coexistence of coeliac disease and hypothyroidism led to diagnostic difficulties and delay of treatment.

A graduate student at Rutgers once looked up the Counsell article above. This is her analysis:

From: Lynda Callicotte Date: 16 Nov 95

Autoimmune hypothyroidism is more common in coeliac patients than Graves disease is. Around 10% of coeliacs had hypothyroidism and there was a high incidence of anti-thyroid antibodies. Anti-thyroid antibodies, unlike Graves antibodies, target the thyroid hormone itself and cause it to be destroyed or to be ineffective. The doctors didn't know why coeliacs should be predisposed to hypothyroidism, but they speculated that maybe the excessive gut permeability results in greater than normal exposure to foreign antigens that resemble thyroid hormone and can trigger an immune response to it. Most coeliacs who had hypothyroidism were elderly and probably had untreated coeliac disease for a long time. The reason why hypothyroidism and coeliac result in diagnosic complications is that some of the symptoms are the same. When one of the two diseases is treated, but the symptoms don't all go away, Page 290 of 399

the doctors are confused. Hypothyroidism can also mask some symptoms of coeliac disease. For instance, coeliacs often have diarrhea, but hypothyroidism can cause constipation.

Cuoco L, Certo M, Jorizzo RA, De Vitis I, Tursi A, Papa A, De Marinis L, Fedeli P, Fedeli G, Gasbarrini G., “Prevalence and early diagnosis of coeliac disease in autoimmune thyroid disorders”, Ital J Gastroenterol Hepatol 1999 May;31(4):283-7

Department of Internal Medicine, Catholic University S.C., Rome, Italy.

BACKGROUND AND AIMS: Coeliac disease is associated with several autoimmune disorders such as insulin-dependent diabetes, Sjogren's syndrome, Addison's disease and thyroid diseases. The aim of our study was to evaluate the prevalence of coeliac disease in patients affected by autoimmune thyroid diseases by means of anti-gliadin and anti-endomysial antibodies. PATIENTS: We studied 92 patients affected by autoimmune thyroid diseases (47 chronic autoimmune thyroiditis, 22 Hashimoto's thyroiditis and 23 Graves' disease). Ninety patients with non autoimmune thyroid disorders (51 multifollicular goitre, 28 solitary nodule and 11 papillary carcinoma) and 236 blood donors also took part in the study as control groups. METHODS: Total serum IgA were measured in all subjects to exclude selective IgA deficiency; then we measured anti-gliadin antibodies and anti-endomysial antibodies. In patients with Page 291 of 399

anti-gliadin/anti-endomysial antibody positivity and/or with haematinic and laboratory signs of malabsorption we carried out gastrointestinal endoscopy with duodenal histological examination. RESULTS: Among the 92 patients with autoimmune thyroid disease, 4 (4.3%) showed anti-gliadin and anti-endomysial positivity and had coeliac disease; among the 90 patients with non autoimmune thyroid diseases, 1 (1.1%) had coeliac disease; finally, among the blood donors, 1 subject (0.4%) was anti-gliadin-anti-endomysium antibody positive and had coeliac disease. Those subjects presenting with only anti-gliadin antibody positivity did not have coeliac disease. CONCLUSIONS: These results show that the prevalence of coeliac disease in patients with autoimmune thyroid diseases is significantly increased when compared with the general population (p = 0.009) but not with patients affected by non autoimmune thyroid disorders (p = 0.18). We suggest a serological screening for coeliac disease in all patients with autoimmune thyroid disease measuring anti-endomysial antibodies, considering that early detection and treatment of coeliac disease are effective in preventing its complications.

Freeman H, "Celiac-associated autoimmune thyroid disease: A study of 16 patients with overt hypothyroidism" 1995; July/Aug 1995, 9(5): 242-246.

In Freeman it says: "Greater small intestinal permeability in celiac disease patients may permit excessive amounts of antigen to enter the circulation and crossreact with other tissues, including the thyroid gland." Page 292 of 399

Scand J Gastroenterol 1988 Nov;23(9):1105-8

Selective vitamin B12 malabsorption in adult coeliac disease. Report on three cases with associated autoimmune diseases.

Stene-Larsen G, Mosvold J, Ly B.

Medical Dept., Lovisenberg Hospital, Olso, Norway.

Three cases of adult coeliac disease with severe vitamin B12 deficiency not accompanied by folate or iron depletion are presented. Two of the patients had the extremely rare combination of coeliac disease and lack of intrinsic factor and autoimmune thrombocytopenic purpura. A close association between coeliac disease and autoimmunity is indicated by the development of autoimmune thyroiditis in the third patient. Vitamin B12 malabsorption caused by coeliac disease is emphasized as a pathogenetic mechanism of megaloblastic anaemia.

Sategna-Guidetti C, Volta U, Ciacci C, Usai P, Carlino A, De Franceschi L, Camera A, Pelli A, Brossa C., Page 293 of 399

"Prevalence of thyroid disorders in untreated adult celiac disease patients and effect of gluten withdrawal: an Italian multicenter study", Am J Gastroenterol 2001 Mar;96(3):751-7

ABSTRACT (University of Torino, Italy)

OBJECTIVES: Many afflictions have been associated with celiac disease, but chance associations may exists. The aim of this study was to establish, by means of a multicenter prospective study, the prevalence of thyroid impairment among adult patients with newly diagnosed celiac disease and to evaluate the effect of a 1-yr gluten withdrawal on thyroid function. METHODS: A total of 241 consecutive untreated patients and 212 controls were enrolled. In 128 subjects a thorough assessment, including intestinal biopsy, was repeated within 1 yr of dietary treatment. Thyroid function was assayed by measuring the levels of TSH, free T3, free T4, thyroperoxidase, and thyroid microsome antibodies. RESULTS: Thyroid disease was 3-fold higher in patients than in controls (p < 0.0005). Hypothyroidism, diagnosed in 31 patients (12.9%) and nine controls (4.2%), was subclinical in 29 patients and of nonautoimmune origin in 21. There was no difference regarding hyperthyroidism, whereas autoimmune thyroid disease with euthyroidism was present in 39 patients (16.2%) and eight controls (3.8%). In most patients who strictly followed a 1-yr gluten withdrawal (as confirmed by intestinal mucosa recovery), there was a normalization of subclinical hypothyroidism. Twenty-five percent of patients with euthyroid autoimmune disease shifted toward either a subclinical hyperthyroidism or subclinical hypothyroidism; in these subjects, dietary compliance was poor. In addition, 5.5% of patients Page 294 of 399

whose thyroid function was normal while untreated developed some degree of thyroid dysfunction 1 yr later. CONCLUSIONS: The greater frequency of thyroid disease among celiac disease patients justifies a thyroid functional assessment. In distinct cases, gluten withdrawal may single-handedly reverse the abnormality.

Sategna-Guidetti C, Bruno M, Mazza E, Carlino A, Predebon S, Tagliabue M, Brossa C., "Autoimmune thyroid diseases and coeliac disease", Eur J Gastroenterol Hepatol 1998 Nov;10(11):927-31

Department of Internal Medicine, Cattedra di Gastroenterologia, Universita' di Torino, Italy.

BACKGROUND: Coeliac disease may be associated with a wide variety of diseases of known or suspected immunological aetiology. OBJECTIVE: To screen for both (a) the prevalence of coeliac disease in adults with autoimmune thyroid diseases, and (b) thyroid impairment among adults with coeliac disease, as compared to sex- and age-matched controls. DESIGN: Prospective cohort study. SETTING: University teaching hospital. PATIENTS: A total of 152 consecutive adults with autoimmune thyroid diseases, 185 consecutive coeliac disease patients (53 newly diagnosed and 132 already on a gluten-free diet) and 170 sex- and age-matched controls. METHODS: Screening for coeliac disease was done by means of IgA anti-endomysium antibodies, detected by indirect Page 295 of 399

immunofluorescence on monkey oesophagus. Patients with positive sera underwent duodenal biopsy for diagnostic confirmation. Thyroid function was assessed by measuring the levels of serum thyroid-stimulating hormone, free T3, free T4, thyroperoxidase and thyroid microsome antibodies. Autoimmune thyroid diseases were classified according to the American Thyroid Association guidelines. RESULTS: Anti-endomysium antibodies were positive in five of 152 autoimmune thyroid disease patients (3.3%) and coeliac disease was histologically confirmed in all: this prevalence is 10-fold higher than expected. Only one patient presented with gastrointestinal complaints, but iron deficiency was found in three and alterations at bone mineralometry in all. The overall prevalence of autoimmune thyroid diseases was significantly higher (38/185, 20.5%) in coeliac patients than in controls (19/170, 11.2%). The prevalence of both hypo- and hyperthyroidism was not different from that of controls, while the prevalence of autoimmune thyroid disease with euthyroidism was 13% in patients and 4.7% in controls. CONCLUSIONS: The association of coeliac disease with autoimmune thyroid disease is not surprising as they share common immunopathogenetic mechanisms. It is advisable to screen autoimmune thyroid disease patients for coeliac disease as there is an increased risk for gluten intolerance. In contrast, thyroid function assessment in coeliac disease patients is probably less justified, although the need for a strict clinical follow-up of those patients with euthyroidism and autoimmune thyroid disease, who could develop overt thyroid impairment, remains an open question.

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Valentino R, Savastano S, Tommaselli AP, Dorato M, Scarpitta MT, Gigante M, Micillo M, Paparo F, Petrone E, Lombardi G, Troncone R., Prevalence of coeliac disease in patients with thyroid autoimmunity", Horm Res 1999;51(3):124-7

CNR, Experimental Endocrinology and Oncology Center (CEOS), Department of Cellular and Molecular Biology and Pathology, University Federico II, Naples, Italy.

The occurrence of autoimmune thyroid disorders among patients with coeliac disease (CD) is well documented, but the exact prevalence of CD among patients with autoimmune thyroid diseases (ATD) is as yet unclear. We screened 150 newly diagnosed patients with ATD by serum endomysial antibody detection (EmA). In 5 subjects (3.3%) EmA positivity was found; all underwent jejunal biopsy. On gluten-free diet an excellent clinical and histological response was recorded with an improvement of hypothyroidism and reduction of the thyroxine dosage. Our data suggest a significant high prevalence (3.3%) of CD in patients with ATD, in particular with Hashimoto's thyroiditis.

Valentino R, Savastano S, Tommaselli AP, Dorato M, Scarpitta MT, Gigante M, Lombardi G, Troncone R., "Unusual association of thyroiditis, Addison's disease, ovarian failure and celiac disease in a young woman", J Endocrinol Invest 1999 May;22(5):390-4

Page 297 of 399

Centro di Endocrinologia e Oncologia Sperimentale del CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Italy.

The coexistence of autoimmune endocrine diseases, particularly autoimmune thyroid disease and celiac disease (CD), has recently been reported. We here present a 23-year-old woman with a diagnosis of hypothyroidism due to Hashimoto's thyroiditis, autoimmune Addison's disease, and kariotypically normal spontaneous premature ovarian failure. Considering the close association between autoimmune diseases and CD, we decided to search for IgA anti-endomysium antibodies (EmA) in the serum. The positivity of EmA and the presence of total villous atrophy at jejunal biopsy allowed the diagnosis of CD. On a gluten-free diet the patient showed a marked clinical improvement accompanied, over a 3-month period, by a progressive decrease in the need for thyroid and adrenal replacement therapies. After 6 months, serum EmA became negative and after 12 months a new jejunal biopsy showed complete mucosal recovery. After 18 months on gluten-free diet, the anti-thyroid antibodies titre decreased significantly, and we could discontinue thyroid substitutive therapy. This case emphasizes the association between autoimmune polyglandular disease and CD; the precocious identification of these cases is clinically relevant not only for the high risk of complications (e.g. lymphoma) inherent to untreated CD, but also because CD is one of the causes for the failure of substitute hormonal therapy in patients with autoimmune thyroid disease.

Page 298 of 399

Ventura A, Neri E, Ughi C, Leopaldi A, Citta A, Not T., "Gluten-dependent diabetes-related and thyroid-related autoantibodies in patients with celiac disease", J Pediatr 2000 Aug;137(2):263-5

Clinica Pediatrica e Laboratorio di Analisi, IRCCS "Burlo Garofolo" Trieste, Trieste, Italy.

Patients with celiac disease are at high risk of having autoimmune disorders. Moreover, untreated patients with celiac disease have been found to have a higher than expected prevalence of organ-specific autoantibodies. In a prospective study of 90 patients with celiac disease, we found that the prevalence of diabetes and thyroid-related serum antibodies was 11.1% and 14.4%, respectively. Like antiendomysium autoantibodies, these organ-specific antibodies seem to be gluten-dependent and tend to disappear during a gluten-free diet.

Volta U, De Franceschi L, Molinaro N, Tetta C, Bianchi FB, "Organ-specific autoantibodies in coeliac disease: do they represent an epiphenomenon or the expression of associated autoimmune disorders?", Ital J Gastroenterol Hepatol 1997 Feb;29(1):18-21

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Department of Internal Medicine, Cardiology and Hepatology, University of Bologna, Italy.

BACKGROUND AND AIMS: The occurrence of autoimmune disorders and organ-specific autoantibodies has been reported in coeliac disease. We assessed the prevalence of organ-specific autoantibodies in coeliac patients and evaluated whether their finding is an expression of associated autoimmune diseases. METHODS: Sera from 70 coeliac disease patients were tested for thyroid microsomal, gastric parietal cell, adrenal cortex and pancreatic islet cell antibodies by indirect immunofluorescence on O blood group human tissues. RESULTS: Eighteen coeliacs (26%) were positive for at least one of the autoantibodies studied; thyroid microsomal antibodies showed a higher prevalence (21%) than parietal cell (11%), adrenal cortex (4%) and islet cell antibodies (3%). In 15 (21%) of the 70 coeliacs studied an association with autoimmune diseases was found, including insulin dependent diabetes mellitus (6 cases), autoimmune hepatitis (3 cases), hypothyroidism (4 cases), thyrotoxicosis (1 case) and dermatomyositis (1 case). One or more organ-specific autoantibodies were positive in 12 (80%) of the 15 coeliacs with autoimmune disorders in comparison with their positivity in 6 (11%) of the 55 coeliacs without autoimmune diseases (p < 0.0001). CONCLUSIONS: The finding of organ-specific autoantibodies in coeliac patients discloses the coexistence of a wide spectrum of immunological diseases.

J Mal Vasc 2001 Jun;26(3):191-5 Page 300 of 399

[Takayasu's disease associated with autoimmune thyroiditis and celiac sprue: clinical course and limitations of treatment]

Korinek J, Lubanda JC, Karetova D, Linhart A, Novakova L, Krivanek J, Aschermann M.

Service de Medecine Interne et Cardio-Vasculaire, CHU, 1re Faculte de Medecine, Universite Charles, U nemocnice 2, 128 00 Prague 2, Republique Tcheque.

Takayasu's arteritis is a non-specific form of vasculitis involving the aorta, its main branches and pulmonary arteries. It is a rare disease in our country, contrasting with the high prevalence in Southeast Asia, Africa and South America. We discuss the course of the disease in our patient who was a young women who developed Takayasu's arteritis associated with autoimmune thyroiditis and malabsorption syndrome due to celiac sprue. Long-term immunosuppressive therapy contributed to stabilizing the associated diseases, but did not stop the progression of the vascular lesions. The main adverse outcome in our patient was the development of severe renovascular hypertension. Bilateral renal artery stenosis was treated by angioplasty with stent implantation. Based on literature reports, the association of Takayasu's disease with multiple autoimmune disorders is a rare event. However, it would appear that the arteritis was the limiting disease for prognosis in our patient. Page 301 of 399

Eur J Pediatr 1995 Oct;154(10):815-8

Isolated cerebral thrombo-embolism and Crohn disease.

Gormally SM, Bourke W, Kierse B, Monaghan H, McMenamin J, Drumm B.

Arterial thrombo-embolism is an unusual complication in inflammatory bowel disease in adults and children. Cerebral arterial disease has been reported on only a few occasions. There are only two previous case reports of arterial disease occurring in a child with Crohn disease. However in both instances the arterial disease was part of a generalised Takayasu arteritis which resulted in multi-organ involvement. This report describes a 14-year-old boy who developed seizures before a histological diagnosis of Crohn disease was made. These seizures were the result of a vascular lesion which was confined to the right middle cerebral artery. CONCLUSION. Crohn disease as well as ulcerative colitis should be considered as a possible cause of cerebrovascular accidents in children.

Page 302 of 399

trombociti

Gastroenterology 1976 Jun;70(6):1042-4

Thrombocytosis in patients with celiac sprue.

Nelson EW, Ertan A, Brooks FP, Cerda JJ.

In 57% of the patients (12 of 25) seen with celiac sprue, as shown by clinical course and small bowel biopsy, peripheral blood thrombocytosis was present (range: 350,000 to 815,000 platelets per mm(3); mean: 546,000 +/- 44,060 SE). After clinical and histological remission, the platelet counts in these patients fell significantly (range: 188,000 to 300,0000 platelets per mm(3); mean 252,750 +/- 13,211 SE). There was no correlation between thrombocytosis and serum iron, folate, or vitamin B12 levels. Celiac sprue joins inflammatory bowel disease among gastrointestinal disorders as a consideration in the differential diagnosis of thrombocytosis. In these patients, thrombocytosis reflected active disease and was not present during remission. Evaluation of peripheral blood platelets may be useful in the assessment of patients with celiac sprue.

Page 303 of 399

Presse Med 1993 Oct 2;22(29):1344-6

[Thrombocytosis of celiac disease in adults: a diagnostic and prognostic marker?]

Dupond JL, de Wazieres B, Flausse-Parrot F, Fest T, Morin G, Closs F, Vuitton D.

Service de Medecine interne, CHU, Besancon.

In 14 of 23 patients seen with coeliac disease thrombocytosis was present (range: 420,000 to 789,000 platelets per cubic mm) and was unrelated to iron deficiency or inflammatory syndrome. Among patients with thrombocytosis (group I), 6 had an associated autoimmune disease; this association was absent in patients without thrombocytosis (group II). There was no correlation between thrombocytosis and lymphocyte count, plasma IgA, IgG, IgM and fibrinogen levels, presence of HLA B8 antigen or histological stage. On the other hand, group I patients had a lower plasma level of albumin, phosphorus and folates. We conclude that thrombocytosis is useful in the assessment of patients with coeliac disease and reflects an enhanced activity of the disease. Moreover, the presence of thrombocytes in these patients' blood may indicate a major risk of associated autoimmune disease.

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Page 305 of 399

Skin

Dasgupta A. Eczema and neurological disorders in association with malabsorption syndrome. Indian J Dermatol. 1969 Apr;14(3):113-4. No abstract available. PMID: 5356646 [PubMed - indexed for MEDLINE]ù

Linear IgA bullous dermatosis responsive to a gluten-free diet.

Egan CA, Smith EP, Taylor TB, Meyer LJ, Samowitz WS, Zone JJ.

Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Salt Lake City, Utah, USA.

Dermatitis herpetiformis is associated with a gluten-sensitive enteropathy in >85% of cases. Both the skin lesions and the enteropathy respond to gluten restriction. Linear IgA bullous dermatosis has a much lower prevalence of histological small bowel abnormalities, and lesions are not known to respond to gluten restriction. We report a patient with linear IgA bullous dermatosis and gluten-sensitive enteropathy. This report addresses the issue of whether linear IgA bullous dermatosis can be associated with gluten-sensitive Page 306 of 399

enteropathy. We evaluated the response to gluten restriction and normal diet by following the status of the patient's jejunal biopsies and skin lesions. The patient responded to gluten restriction, as shown by resolution of jejunal abnormalities and skin lesions and subsequently by recurrence of jejunal abnormalities and skin lesions with reinstitution of a gluten-containing diet. This report demonstrates that linear IgA bullous dermatosis can respond to gluten restriction if an underlying gluten-sensitive enteropathy is present.

Scala E, Giani M, Pirrotta L, Guerra EC, De Pita O, Puddu P. Urticaria and adult celiac disease. Allergy. 1999 Sep;54(9):1008-9. No abstract available. PMID: 10505471 [PubMed - indexed for MEDLINE]

Page 307 of 399

shortstature

N Z Med J 1983 Jul 27;96(736):563-5

Familial short stature and coeliac disease: a family case report.

Gilchrist N, Espiner EA, Cook HB.

A case of coeliac disease associated with growth retardation and pubertal failure in a 19 year old female is reported. Diagnosis was delayed by use of the term 'undiagnosed short stature'. Investigations confirmed severe malabsorption, osteoporosis and marked delay in bone growth associated with small bowel mucosal atrophy. HLA screening of the patient's family led to the identification of coeliac disease in her brother aged 12 years and her asymptomatic mother both of whom were short in stature. The institution of a gluten free diet, appropriate vitamin and mineral supplements has restored growth and sexual development to normal in the affected children. These cases emphasize the variable nature of coeliac disease, its familial occurrence and the need to exclude the disorder in cases of undiagnosed (familial) short stature.

Page 308 of 399

transit

Perri F, Pastore M, Zicolella A, Annese V, Quitadamo M, Andriulli A., "Gastric emptying of solids is delayed in celiac disease and normalizes after gluten withdrawal", Acta Paediatr 2000 Aug;89(8):921-5

Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy. [email protected]

Several gastrointestinal motor abnormalities have been detected in patients with celiac disease, but it is unclear whether they are able to influence the gastric emptying rate. The aim of this work was to evaluate the gastric emptying rate of solids in children with celiac disease before and after a gluten-free diet. Nine children with celiac disease and nine healthy controls (age range 4-16 y) underwent a 13C-octanoic acid breath test to measure gastric emptying. Half emptying time (t1/2) and lag phase (t(lag)) were calculated. After 6 mo of a gluten-free diet, all celiac children underwent a repeat 13C-octanoic acid breath test. The gastric motility parameters, t1/2 and t(lag), were significantly longer in patients than in controls. No significant correlation between abnormal gastric emptying and specific symptom patterns or severity of histological damage was found. On a gluten-free diet, the gastric emptying rate normalized in all celiac patients. This finding supports the hypothesis that gluten-driven mucosal Page 309 of 399

inflammation might determine motor abnormalities by affecting smooth muscle contractility or impairing the release of neurotransmitters. Alternatively, nutrient malabsorption might determine significant changes in intraluminal milieu, which, in turn, may affect intestinal motor functions. CONCLUSION: patients affected by celiac disease have a markedly delayed gastric emptying of solids, which returns to normal after gluten withdrawal.

Dig Dis Sci 1997 Oct;42(10):2100-5

Gluten-free diet normalizes mouth-to-cecum transit of a caloric meal in adult patients with celiac disease.

Chiarioni G, Bassotti G, Germani U, Battaglia E, Brentegani MT, Morelli A, Vantini I.

Divisione di Riabilitazione Gastroenterologica, Ospedale Clinicizzato di Valeggio sul Mincio, Universita degli Studi di Verona, Italy.

The mechanisms responsible for bowel disturbances in celiac disease are still relatively unknown. Recent reports suggested that small bowel motor abnormalities may be involved in this pathological condition; however, there are no studies addressing small bowel transit in celiac disease before and after a gluten-free diet. We studied the mouth-to-cecum transit time of Page 310 of 399

a caloric liquid meal in a homogeneous group of celiac patients presenting with clinical and biochemical evidence of malabsorption and complaining of diarrhea. Sixteen patients were recruited and investigated by means of hydrogen breath test through ingestion of 20 g lactulose together with an enteral gluten-free diet formula. A urinary D-xylose test was also done in each patient. Both breath tests and D-xylose tests were carried out basally and after a period of gluten-free diet. Twenty healthy volunteers were recruited as a control group and underwent the same breath testing. At the time of the diagnosis, mouth-to-cecum transit time was significantly prolonged in celiacs with respect to controls (243 +/- 10 vs 117 +/- 6 min, P = 0.0001). The D-xylose test was also abnormal (average urinary concentration 2.8 +/- 0.25 g, normal values >4.5). No correlation was found in patients between mouth-to-cecum transit time and urinary D-xylose output (r = 0.22). After the gluten-free diet period, mouth-to-cecum transit time in celiacs was significantly reduced compared to prediet transit (134 +/- 8 vs 243 +/- 10 min, P = 0.0001) and did not show statistical difference when compared to that found in controls (P = 0.1). The D-xylose test reverted to normal in all but two subjects, who were found to be noncompliant with the diet. Mouth-to-cecum transit time is significantly prolonged in patients affected by untreated celiac disease when compared to healthy controls. This alteration might not be correlated to intestinal malabsorption, and the prolonged orocecal transit could be due to impaired small bowel function (deranged motility?). Since intestinal transit returned to normal values after an adequate gluten-free period, a link with severe active mucosal lesions is suggestive. Page 311 of 399

Levine A, Dalal I, Bujanover Y., "Celiac disease associated with familial chronic urticaria and thyroid autoimmunity in a child", Pediatrics 1999 Aug;104(2):e25

Pediatric Gastroenterology Unit, E Wolfson Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

An 11-year-old girl presented with chronic urticaria (CU), antithyroid antibodies, and anemia. Celiac disease was diagnosed. The family history was positive for maternally derived CU and thyroid autoimmunity in three generations. Human leukocyte antigen typing disclosed human leukocyte antigen DQA1*0501 DQB1*0201 in both mother and child. CU was unresponsive to a gluten-free diet despite clinical and laboratory resolution of celiac disease in contrast to previous reports in adults. We believe that this is the first report of this association in a child, highlighting that CU may be a part of the spectrum of autoimmune phenomenon related to celiac disease.

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celiac2 schizophrenia

J Intern Med. 1997 Nov;242(5):421-3.

Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet.

De Santis A, Addolorato G, Romito A, Caputo S, Giordano A, Gambassi G, Taranto C, Manna R, Gasbarrini G.

Department of Internal Medicine, Catholic University, Rome, Italy.

A 33-year-old patient, with pre-existing diagnosis of 'schizophrenic' disorder, came to our observation for severe diarrhoea and weight loss. Use of single photon emission computed tomography, (99mTc)HMPAO SPECT, demonstrated hypoperfusion of the left frontal brain area, without evidence of structural cerebral abnormalities. Jejunal biopsy showed villous atrophy. Antiendomysial antibodies were present. A gluten-free diet was started, resulting in a disappearence of psychiatric symptoms, and normalization of histological duodenal findings and of (99mTc)HMPAO SPECT pattern. This is the first case in which, in an undiagnosed and Page 313 of 399

untreated coeliac patient with psychiatric manifestations, the (99mTc)HMPAO SPECT demonstrated a dysfunction of frontal cortex disappearing after a gluten-free diet.

Curtis Dohan è un pioniere nella terapia dei disturbi psichiatrici con un regime senza glutine [Dohan 1966 e 1969] e pubblica un'opera documentata secondo cui i disturbi psicotici sono virtualmente non esistenti nelle culture dove i grani glutinosi non sono consumati [Dohan 1984].

Dohan FC., "Schizophrenia, cereal grains, and celiac disease", Del Med J. 1973 Oct;45(10):303-4

a questo proposito....

Page 314 of 399

Dohan FC., "Wheat "consumption" and hospital admissions for schizophrenia during World War II. A preliminary report", Am J Clin Nutr. 1966 Jan;18(1):7-10.

Dohan FC, Grasberger JC, Lowell FM, Johnston HT Jr, Arbegast AW., "Relapsed schizophrenics: more rapid improvement on a milk- and cereal-free diet", Br J Psychiatry. 1969 May;115(522):595-6

Dohan FC, Grasberger JC., "Relapsed schizophrenics: earlier discharge from the hospital after cereal-free, milk-free diet", Am J Psychiatry. 1973 Jun;130(6):685-8.

Dohan FC, Levitt DR, Kushnir LD., "Abnormal behavior after intracerebral injection of polypeptides from wheat gliadin: possible relevance to schizophrenia", Pavlov J Biol Sci. 1978 Apr-Jun;13(2):73-82.

Dohan FC., "Celiac-type diets in schizophrenia", Am J Psychiatry. 1979 May;136(5):732-3

Dohan FC., "Hypothesis: genes and neuroactive peptides from food as cause of schizophrenia", Adv Biochem Psychopharmacol. 1980;22:535-48. R Page 315 of 399

Jansson B, Kristjansson E, Nilsson L., [Schizophrenic psychosis disappearing after patient is given gluten-free diet], Lakartidningen. 1984 Feb 8;81(6):448-9

..ma ovviamente il sistema medico- farmaceutico stava cercando un farmaco brevettabile, non una soluzione.

Singh MM, Kay SR., "Letter: Gluten and schizophrenia", Lancet. 1976 Sep 25;2(7987):689-90

Singh MM, Kay SR., "The problem of type II error in the "gluten hypothesis", Am J Psychiatry. 1983 May;140(5):644-5.

Singh MM, Kay SR., "Wheat gluten as a pathogenic factor in schizophrenia", Science. 1976 Jan 30;191(4225):401-2.

Schizophrenics maintained on a cereal grain-free and milk-free diet and receiving optimal treatment with neuropleptics showed an interruption or reversal of their therapeutic progress Page 316 of 399

during a period of "blind" wheat gluten challenge. The exacerbation of the disease process was not due to variations in neuroleptic doses. After termination of the gluten challenge, the course of improvement was reinstated. The observed effects seemed to be due to a primary schizophrenia-promoting effect of wheat gluten.

Singh MM, Kay SR., "Nosological and prognostic distinctions in schizophrenia: pharmacological validation in terms of therapeutic antagonism between anticholinergic anti-parkinsonism drugs and neuroleptics", Neuropsychobiology. 1978;4(5):288-304.

In studying the relationships between anticholinergic-neuroleptic interactions and the nosological and prognostic distinctions in schizophrenia, we have shown that these distinctions have clinicopathological meaning. The countertherapeutic anticholinergic effects seemed to be particularly evident in the good outcome, schizophreniform cases and differentiated between the three diagnostic subtypes. Such effects were most conspicuous in the catatonics who also had the most favorable prognosis, while the paranoids differed from others in not only showing the least anticholinergic effects but also in not conforming to the relationship between these effects and prognosis. The findings are briefly considered in relation to those with wheat gluten which has also been shown to be a countertherapeutic factor in schizophrenia in another study. Page 317 of 399

Ashkenazi A, Krasilowsky D, Levin S, Idar D, Kalian M, Or A, Ginat Y, Halperin B., "Immunologic reaction of psychotic patients to fractions of gluten", Am J Psychiatry. 1979 Oct;136(10):1306-9.

Production of a leukocyte migration inhibition factor by peripheral blood lymphocytes in response to challenge with gluten fractions was studied in hospitalized patients with schizophrenia and other psychoses compared with normal individuals and with children and adolescents with celiac disease. The schizophrenic and other psychotic patients could be subdivided into two groups, one that responded in the leukocyte migration inhibition factor test as the celiac patients did and one that responded as the normal control subjects did. The psychotic and schizophrenic patients did not show any evidence of malabsorption. The authors speculate that gluten may be involved in biological processes in the brain in certain psychotic individuals.

Ashkenazi A, Levin S, Krasilowsky D., "Gluten and autism", Lancet. 1980 Jan 19;1(8160):157.

Page 318 of 399

Ross-Smith P, Jenner FA., "Diet (gluten) and schizophrenia", J Hum Nutr. 1980 Apr;34(2):10712.

Four aspects of clinical evidence for an association between gluten and schizophrenia are examined. The scientific evidence for the role of gluten is set out. Finally, reference is made to other dietary approaches.

Mycroft FJ, Wei ET, Bernardin JE, Kasarda DD., "MIF-like sequences in milk and wheat proteins", N Engl J Med. 1982 Sep 30;307(14):895.

celiac colesterol lathosterol

Br J Nutr. 1985 Jan;53(1):25-30.

The effect of amino-acid-supplemented wheat gluten on cholesterol metabolism in the rat. Page 319 of 399

Bassat M, Mokady S.

The effect of lysine- and threonine-supplemented wheat gluten on cholesterol metabolism was studied using male weanling rats. Animals were fed on cholesterol-free diets containing 100 or 200 g gluten/kg with or without amino acid supplementation, and compared with animals given 50, 100 and 200 g casein/kg diets, for 3 weeks. A hypocholesterolaemic effect observed with the wheat gluten-fed rats, compared with the animals given 100 and 200 g casein/kg diets, was accompanied by increased turnover of cholesterol as expressed by enhanced cholesterol biosynthesis and increased faecal excretion of cholesterol and bile acids. This effect was not abolished by lysine and threonine supplementation. Low levels of blood cholesterol were also observed in the rats fed on the 50 g casein/kg diet. However, a different mechanism, related to impairment of cholesterol transport from the liver, was most likely responsible for the hypocholesterolaemia found in these protein-malnourished animals. The effect on cholesterol metabolism produced by dietary wheat gluten was independent of the low quality of the protein and of its specific deficiency in lysine and threonine.

Page 320 of 399

Mokady S, Einav P., "Effect of dietary wheat gluten in lipid metabolism in growing rats", Nutr Metab. 1978;22(3):181-9.

The effect of dietary wheat gluten on liver and spleen lipogenesis in rats was studied in vitro and in vivo. Weanling rats were fed for 2 or 3 weeks an experimental diet containing wheat gluten as the only protein source and compared to other rats fed a casein control diet. Rats fed gluten showed enhanced in vitro lipogenesis as measured by conversion of (1(-14) C)acetate into liver and spleen lipids. These results indicated that the gluten-fed rats had a significantly higher hepatic capacity than the control rats to synthesize all lipid classes. On the other hand, the in vivo study of hepatic lipogenesis showed smaller differences between the group fed gluten and that fed casein. This suggests that the accumulation of lipids in fatty livers of gluten-fed rats is mostly due to increased rate of biosynthesis and not a result of impairment in the lipids' transport system. In the spleens of the gluten-fed groups, the enhanced in vitro lipogenesis was also found in vivo, indicating that accumulation of lipids in fatty spleens may be a result of biosynthesis only, with no other effects that can take place in vivo.

anche in obesità Page 321 of 399

Menendez R, Arruzazabala L, Mas R, Del Rio A, Amor AM, Gonzalez RM, Carbajal D, Fraga V, Molina V, Illnait J., "Cholesterol-lowering effect of policosanol on rabbits with hypercholesterolaemia induced by a wheat starch-casein diet", Br J Nutr. 1997 Jun;77(6):923-32.

Department of Pharmacology, National Center for Scientific Research, Havana, Cuba.

The effect of policosanol, a mixture of high-molecular-weight aliphatic alcohols isolated from sugarcane wax, on casein-induced hypercholesterolaemia in rabbits was studied. When policosanol was administered by the oral route once daily for 30 d (50 mg/kg) the increases in plasma total cholesterol and LDL-cholesterol (LDC-C) were significantly reduced when compared with the control group. The incorporation of 3H2O into sterols in the liver was significantly depressed, suggesting inhibition of hepatic cholesterol biosynthesis. The oral administration of policosanol raised the rate of removal of 125I-labelled LDL from serum. Kinetic parameters calculated following injection of [125I]LDL showed than in casein-fed rabbits, the terminal half-life (t1/2) was significantly decreased after policosanol treatment. The Page 322 of 399

hepatic LDL-binding activity was increased after policosanol administration which suggested that the enhanced clearance was due, at least in part, to increased receptor-mediated uptake of LDL by the liver. Considered together, these results suggest that policosanol can significantly reduce the increase of plasma LDL-C in rabbits fed on a wheat starch-casein diet by reducing cholesterol biosynthesis in the liver. Such an effect could account for the enhancement of LDL catabolism through the receptor-mediated pathway.

Chao YS, Kroon PA, Yamin TT, Thompson GM, Alberts AW., "Regulation of hepatic receptordependent degradation of LDL by mevinolin in rabbits with hypercholesterolemia induced by a wheat starch-casein diet", Biochim Biophys Acta. 1983 Nov 29;754(2):134-41.

Rabbits fed a wheat starch-casein diet develop a marked hypercholesterolemia and have a slower rate of removal of rabbit 125I-labeled low density lipoproteins (LDL) from plasma. Treating rabbits with mevinolin, a highly potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, at a daily dose of 20 mg per animal prevents the increase in plasma and LDL cholesterol. The mevinolin effect is mediated through an increased rate of removal of rabbit 125I-labeled LDL from plasma. To study the role of mevinolin on the Page 323 of 399

regulation of the hepatic LDL receptor in rabbits, the binding of 125I-labeled LDL and 125I-labeled beta-VLDL (beta-migrating very-low-density lipoproteins) to liver membranes prepared from rabbits fed the wheat starch-casein diet with or without mevinolin was investigated. Liver membranes from wheat starch-casein-fed rabbits have no demonstrable EDTA-sensitive binding activity of 125I-labeled LDL and low (37 ng/mg protein) binding activity of 125I-labeled beta-VLDL. Treatment of the wheat starch-casein fed rabbits with mevinolin results in high levels of specific EDTA-sensitive binding of 125I-labeled LDL (28.7 ng/mg protein) and 125I-labeled beta-VLDL (120 ng/mg protein). To assess the functional role of the hepatic LDL receptor in response to mevinolin, the catabolism of 125I-labeled LDL by perfused rabbit livers was studied. Perfused livers from mevinolin-treated rabbits show a 3.3-fold increase in the rate of receptor-dependent catabolism of 125I-labeled LDL (4.6% X h-1) when compared with that of livers from rabbits not treated with mevinolin (1.4% X h-1). Thus, these studies demonstrate that mevinolin prevents the increase of plasma LDL cholesterol level in rabbits fed a wheat starch-casein diet by regulating the levels of hepatic LDLbinding sites and the rate of receptor-dependent catabolism of LDL by the liver.

Page 324 of 399

Menendez R, Mas R, Perez J, Gonzalez RM, Jimenez S., "Oral administration of D-003, a mixture of very long chain fatty acids prevents casein-induced endogenous hypercholesterolemia in rabbits", Can J Physiol Pharmacol. 2004 Jan;82(1):22-9.

Center of Natural Products, National Center for Scientific Research, PO Box 6880, Havana, Cuba. [email protected]

D-003 is a mixture of very long chain saturated fatty acids (VLCSFA) purified from sugar cane wax with cholesterol-lowering effects proven in animal models and healthy volunteers. D-003 inhibits cholesterol biosynthesis through the regulation of HMG-CoA reductase activity. Rabbits fed diets enriched with casein develop endogenous hypercholesterolemia (EH), making them a very useful model for determining the mechanism of action of drugs affecting lipids. We examined whether D-003 prevented EH. Rabbits were fed a casein diet for 4 weeks, administered simultaneously with D-003 (5, 50, and 100 mg.kg-1.day-1). As expected, nontreated rabbits became hypercholesterolemic; however, as early as 15 days following administration, the treated group (50 and 100 mg.kg-1.day-1) had significantly decreased total cholesterol and low-density lipoprotein cholesterol (LDL-C). Triglycerides were not affected; however, at study completion, Page 325 of 399

HDL-C levels significantly increased at all the doses assayed. D-003 inhibited de novo synthesis of cholesterol, since the incorporation of 3H2O into sterols in the liver and proximal small bowel was significantly depressed. Also, D-003 significantly raised the rate of removal of [125I]-LDL from serum and significantly elevated [125I]-LDL binding activity to liver homogenates. Taken together, these results show that the efficacy of D-003 in reducing casein-derived hypercholesterolemia could involve, at least partially, an inhibition of hepatic cholesterol biosynthesis, which may elicit a decreased cholesterol concentration in hepatocytes, preventing the loss of hepatic LDL receptors induced by casein administration. However, since casein-induced hypercholesterolemia is also a consequence of a stimulation of cholesterol absorption in the lumen and an increase of the output of cholesterol associated with LDL, the effect of D-003 on cholesterol absorption and LDL synthesis by the liver should be investigated.

peptidi opioidi

Biochim Biophys Acta. 1986 May 21;876(3):392-8.

Page 326 of 399

Secretion of cholesteryl-ester-rich lipoproteins by the perfused livers of rabbits fed a wheatstarch-casein diet.

Chao YS, Yamin TT, Seidenberg J, Kroon PA.

Rabbits fed a cholesterol-free semi-synthetic wheat-starch-casein diet had a high plasma cholesterol concentration; most of the cholesterol was associated with low-density lipoproteins (LDL). Chemical analyses of plasma lipoproteins revealed that very-low-density lipoproteins (VLDL), intermediate lipoproteins and LDL from casein-fed rabbits contained more cholesteryl ester than that of lipoproteins isolated from chow-fed animals. The fatty acid composition of cholesteryl esters of plasma lipoproteins showed that there were higher contents of oleic acid than linoleic acids in lipoproteins from casein-fed rabbits. Lipoproteins isolated from liver perfusates of casein-fed rabbits had higher cholesteryl oleate content than lipoproteins from chow-fed rabbit liver perfusates. There was a marked increase in secretion of apolipoproteins from perfused livers of casein-fed rabbits. We conclude that the high levels of plasma cholesterol in casein-fed rabbits are of hepatic origin and that one of the hypercholesterolemic actions of dietary casein in rabbits is the induction of hepatic synthesis and secretion of cholesteryl-ester-rich lipoproteins.

Page 327 of 399

Chiari A, Lovisolo P, Fogliatto G, Fancelli D, Ghiselli G., "Correction of dyslipoproteinaemia of casein-fed rabbit by FCE 27677, a potent novel ACAT inhibitor", Pharmacol Res. 1996 Mar;33(3):181-9.

Pharmacia Farmitalia Carlo Erba, Cardiovascular Department, Nerviano, Italy.

Rabbits fed a wheat starch casein diet develop hypercholesterolaemia characterized by the plasma elevation of low density lipoprotein (LDL) that is caused by oversecretion of apoB-100 containing lipoproteins by the liver and by the suppression of the EDTA-sensitive hepatic betavery low density lipoprotein (VLDL)-LDL receptor. In this study, the effect of FCE 27677 ((-)N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2-(4-dimethylaminoph eny l)-4,5-dimethyl-dioxolan-2-yl]methylurea) a novel potent systemic acylCoA:cholesterol acetyltransferase (ACAT, EC 2.3.1.26) inhibitor, has been evaluated. When New Zealand White rabbits were fed with casein for 4 weeks, LDL cholesterol increased from 14 +/- 3 mg/dl-1 to 77 +/- 6 mg/dl-1. By contrast the animals receiving FCE 27677 (10 mg kg-1 d-1) mixed with the casein diet maintained a normal LDL concentration (22 +/- 3 mg dl-1). This hypolipidaemic Page 328 of 399

effect was also observed when rabbits previously made hypercholesterolaemic by being fed casein for 4 weeks were then treated for a month with FCE 27677. [125I]LDL plasma turnover studies and [125I]LDL binding studies to liver membranes were carried out with the purpose of investigating the mechanism of action of the drug. The LDL apoB-100 production rate in chow-fed, casein-fed, and casein-fed rabbits receiving FCE 27677, was respectively 10.5, 22.4, and 12.5 mg kg-1 d-1. The turnover rate of [125I]LDL in the animals receiving the drug was not, however, different from that in the rabbits fed the casein diet alone (2.381 vs 2.079 pools d-1). Both values were lower than that in chow-fed animals (3.271 pools d-1). FCE 27677 did not normalize the activity of the hepatic beta-VLDL-LDL EDTA-sensitive receptor which is suppressed by casein feeding. Altogether the results are consistent with the idea that FCE 27677 by acting through inhibition of the cholesterol esterification in the liver normalizes the LDL synthetic rate. ACAT inhibitors may be useful drugs for the treatment of human dyslipoproteinaemia secondary to derangement of the apoB-100 synthetic rate.

Samman S, Khosla P, Carroll KK., "Effects of dietary casein and soy protein on metabolism of radiolabelled low density apolipoprotein B in rabbits", Lipids. 1989 Mar;24(3):169-72. Page 329 of 399

Department of Biochemistry, University of Western Ontario, London, Canada.

Rabbits fed semipurified diets containing casein have elevated plasma cholesterol levels compared to those fed soy protein. As part of continuing studies on the mechanism of casein-induced hypercholesterolemia, two groups of six rabbits were fed these diets for 14 to 16 weeks. Animals fed the casein diet were found to have significantly higher plasma concentrations of protein, cholesterol, triacylglycerol, phospholipid and apolipoprotein B (apo B) associated with low density lipoprotein (LDL) than those fed the soy protein diet. Kinetic studies showed that the fractional catabolic rate of LDL-apo B was significantly lower in animals fed casein than in those fed soy protein regardless of whether the tracer LDL was obtained from donors fed casein or soy protein. The production rate of LDL-apo B was higher in casein-fed animals but this was not statistically significant. These results show that the efficiency of removal of LDL is significantly reduced in animals fed casein compared to those fed soy protein, and that the source of LDL did not affect the efficiency of its subsequent removal. The accumulation of LDL in casein-fed animals is consistent with down-regulation of the LDL receptor.

free Page 330 of 399

Harders-Spengel K, Wood CB, Thompson GR, Myant NB, Soutar AK., Difference in saturable binding of low density lipoprotein to liver membranes from normocholesterolemic subjects and patients with heterozygous familial hypercholesterolemia", Proc Natl Acad Sci U S A. 1982 Oct;79(20):6355-9.

To investigate the possible role of the low density lipoprotein (LDL) receptor in the catabolism of LDL by the human liver, the binding of 125I-labeled LDL to membrane fractions prepared from human liver biopsies was determined. Biopsy samples taken for routine histology were obtained from seven patients with heterozygous familial hypercholesterolemia, one with non-familial hypercholesterolemia, and seven normocholesterolemic subjects. LDL was bound by the membranes from normal subjects in a saturable manner that was inhibited by 56% in the presence of excess LDL. Binding of LDL was also inhibited by modification of the lipoproteins with 1,2-cyclohexanedione. The amount of 125I-labeled LDL bound to membranes from familial hypercholesterolemic livers that could be displaced with excess LDL was significantly less than that bound by normocholesterolemic membranes. These observations suggest that LDL receptors are expressed in normal human liver and are defective in the livers of familial hypercholesterolemic patients.

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Chao Y, Yamin TT, Alberts AW., "Effects of cholestyramine on low density lipoprotein binding sites on liver membranes from rabbits with endogenous hypercholesterolemia induced by a wheat starch-casein diet", J Biol Chem. 1982 Apr 10;257(7):3623-7.

Rabbits fed a wheat starch-casein diet develop a marked hypercholesterolemia with a lipoprotein distribution similar to that of humans. Approximately 76% of the total cholesterol is carried in the low density lipoprotein (LDL) fraction (1.006 less than d less than 1.063 g/ml). Inclusion of 1% cholestyramine in the diet prevents the increase in plasma cholesterol. The cholestyramine effect is mediated through an increased fractional catabolic rate of 125I-LDL. In order to determine the potential role of hepatic LDL receptors in the removal of LDL from the plasma, binding of 125I-LDL and 125I-beta-VLDL (beta-migrating very low density lipoproteins) to hepatic membranes prepared from livers of rabbits fed the wheat starch-casein diet with or without cholestyramine supplementation was investigated. Membranes from livers of the cholestyramine-supplemented animals exhibit high levels of specific EDTAsensitive binding of either of the 125I-labeled lipoproteins. Very little EDTA-sensitive binding occurs on liver membranes from wheat starch-casein-fed rabbits that have not been treated with cholestyramine. These results indicate that the hypercholesterolemia in rabbits associated with the wheat starch-casein diet is wholly or partially the result of a decreased number of specific hepatic LDL

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receptors and thus a decreased catabolism of plasma cholesterol. The response of the liver to the inclusion in the diet of the bile acid sequestrant, cholestyramine, is to maintain or increase the number of specific LDL binding sites, thus promoting catabolism of plasma cholesterol.

Am J Clin Nutr. 1997 Aug;66(2):357-65.

Postprandial lipemia in relation to sterol and fat excretion in ileostomy subjects given oat-bran and wheat test meals.

Lia A, Andersson H, Mekki N, Juhel C, Senft M, Lairon D.

Department of Clinical Nutrition, University of Goteborg, Sweden. [email protected]

To investigate the mechanisms behind the serum cholesterol-lowering effect of oat fiber, we simultaneously measured postprandial lipid responses, serum lathosterol concentrations, and small bowel excretion of fat and sterols in ileostomy subjects given test meals high or low in oat fiber. Page 333 of 399

Six ileostomy subjects (three women and three men) were served an oat-bran test meal (OB; 16.3 g fiber) and a wheat test meal (6.3 g fiber) in random order. After the postprandial 7-h period, a controlled, low-fat, cholesterol-free diet was served and ileostomy effluent was sampled throughout the 24-h period. Bile acid and fat excretion (24 h) increased by 93% and 146%, respectively (P < 0.05), and total and endogenous cholesterol excretion decreased by 14% and 19%, respectively (P < 0.05), after the OB test meal. The change in hepatic cholesterol synthesis was strongly related to the change in bile acid excretion (Spearman r = 0.89, P < 0.02). The postprandial chylomicron lipid concentration tended to be lower after the OB test meal (-43% for cholesterol, P = 0.07) whereas there was no difference in cholesterol absorption measured by isotope in five subjects. The main effect of the viscous oat betaglucan seems to be related to increased bile acid excretion and subsequent changes in synthesis and endogenous excretion of cholesterol. An additional effect may have been a delay in the micellar lipid solubilization process and a consequent reduction in the secretion of chylomicrons into the circulation

Am J Clin Nutr. 1992 Jan;55(1):81-8. Page 334 of 399

Effects of oat bran, rice bran, wheat fiber, and wheat germ on postprandial lipemia in healthy adults.

Cara L, Dubois C, Borel P, Armand M, Senft M, Portugal H, Pauli AM, Bernard PM, Lairon D.

Unite 130-INSERM (National Institute of Health and Medical Research), Marseille, France.

Six normolipidemic males ingested on separate days a low-fiber test meal [2.8 g dietary fiber (TDF)] containing 70 g fat and 756 mg cholesterol, enriched or not with 10 g TDF as oat bran, rice bran, or wheat fiber or 4.2 g TDF as wheat germ. Fasting and postmeal blood samples were obtained for 7 h and chylomicrons were isolated. Adding fibers to the test meal induced no change in serum glucose or insulin responses. The serum triglyceride response was lower (P less than or equal to 0.05) in the presence of oat bran, wheat fiber, or wheat germ and chylomicron triglycerides were reduced with wheat fiber. All fiber sources reduced chylomicron cholesterol. Cholesterolemia decreased postprandially for 6 h and was further lowered in the presence of oat bran. Serum apolipoprotein (apo) A-1 and apo B concentrations were not affected. Thus, dietary fibers from cereals may reduce postprandial lipemia in humans to a variable extent. Page 335 of 399

Hum Nutr Clin Nutr. 1986 Nov;40(6):429-40.

Effect of wheat bran and pectin on bile acid and cholesterol excretion in ileostomy patients.

Bosaeus I, Carlsson NG, Sandberg AS, Andersson H.

The effect of addition of pectin or wheat bran to a constant low-fibre diet on bile acid and cholesterol excretion from the small intestine has been studied in ileostomy patients. The study was designed to minimize bacterial alteration of ileostomy contents. An addition of 15 g of citrus pectin increased bile acid excretion by 35 per cent (P less than 0.05) and net cholesterol excretion by 14 per cent (P less than 0.05) in six patients, while 16 g of wheat bran to another six patients caused no consistent change. Ileostomy fat excretion increased on the diet with added pectin (P less than 0.05) but not on that with bran. The results support the concept of dietary fibre exerting its effects on lipid metabolism by altering intestinal excretion of sterols.

Am J Clin Nutr. 1999 Jan;69(1):55-63. Page 336 of 399

Postprandial lipid, glucose, insulin, and cholecystokinin responses in men fed barley pasta enriched with beta-glucan.

Bourdon I, Yokoyama W, Davis P, Hudson C, Backus R, Richter D, Knuckles B, Schneeman BO.

Department of Nutrition, University of California, Davis 95616-8571, USA.

BACKGROUND: Fiber regulates the rate and site of lipid and carbohydrate digestion and absorption and thus can modify the alimentary responses to a meal. When fiber sources containing viscous polysaccharides are included in a meal, a slower rate of carbohydrate and lipid absorption will modify the alimentary hormone and lipid responses. OBJECTIVE: We investigated in 11 healthy men the response of insulin, glucose, cholecystokinin, and lipid to 2 test meals containing beta-glucan. DESIGN: One of the meals was high in fiber (15.7 g) and the other meal was low in fiber (5.0 g). The low-fiber meal contained pasta made with wheat flour. The high-fiber meals contained pasta prepared by replacing 40% of the wheat with 2 types of barley flour: barley naturally high in beta-glucan and the other a flour enriched in betaglucan during processing. RESULTS: Plasma glucose and insulin concentrations increased significantly after all Page 337 of 399

meals but the insulin response was more blunted after the barley-containing meals. The test meals were low in fat (25% of energy) but elicited an increase in plasma triacylglycerol and cholecystokinin. Cholecystokinin remained elevated for a longer time after the barley-containing meals. After the low-fiber meal, plasma cholesterol concentrations did not change significantly; however, 4 h after the barley-containing meals, the cholesterol concentration dropped below the fasting concentration and was significantly lower than that after the low-fiber meal. CONCLUSIONS: Carbohydrate was more slowly absorbed from the 2 high-fiber meals. Consumption of the barley-containing meals appeared to stimulate reverse cholesterol transport, which may contribute to the cholesterol-lowering ability of barley.

Gut. 1986 Nov;27(11):1312-9.

Serum cholesterol precursor sterols in coeliac disease: effects of gluten free diet and cholestyramine.

Vuoristo M, Miettinen TA.

Enhanced biliary secretion and high faecal excretion of cholesterol are associated with increased

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cholesterol synthesis in coeliac disease. We have further investigated cholesterol synthesis in coeliac disease by determining the concentrations of faecal steroids and cholesterol precursors in serum, with and without a gluten free diet and while taking cholestyramine. The levels of unesterified methyl sterols and free and esterified lathosterol, but not those of squalene and desmosterol, were increased in proportion to the level of cholesterol synthesis, as measured with the sterol balance technique. Serum esterified methyl sterol concentrations were also slightly higher but, unlike free methyl sterols or lathosterol, they were not significantly correlated with cholesterol synthesis. The gluten free diet decreased the level of cholesterol synthesis, and the levels of lathosterol and free methyl sterols. There was less decrease in the concentration of esterified methyl sterols, and an insignificant decrease in the concentrations of squalene and desmosterol. Cholestyramine lowered the serum cholesterol concentration and increased that of serum free methyl sterols less in the patients than in the controls, and the increase was proportionate to increase of cholesterol elimination (or synthesis). The increase of serum free methyl sterols per unit of the increase of cholesterol elimination (or synthesis) was three times higher in the bile acid malabsorption caused by cholestyramine than in the cholesterol

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malabsorption caused by gluten enteropathy. On the other hand, the decrease in the level of serum cholesterol relative to the increase in cholesterol elimination (or synthesis) was higher in cholesterol malabsorption due to coeliac disease than in cholestyramine induced bile acid malabsorption. Effective secretion of newly synthesised and/or absorbed cholesterol directly into the bile could be a factor in the marked decrease of the serum cholesterol concentration in coeliac disease.

Eur J Clin Invest. 1982 Aug;12(4):285-91. Cholesterol absorption, elimination and synthesis in coeliac disease. Vuoristo M, Miettinen TA.

Hypocholesterolaemia and high faecal elimination of cholesterol was explored by measuring the percentage of cholesterol absorbed, faecal steroids, serum cholesterol and dietary cholesterol in patients with coeliac disease before and after a gluten free diet. From these data, the total and endogenous flux of cholesterol into the gut and the amount of cholesterol absorbed could be calculated. The mean faecal bile acid excretion was normal, but faecal endogenous steroids and

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thus faecal total steroids, and the cholesterol synthesis, were increased in the patients. The percentage of cholesterol absorbed was quite low (15.1 +/- 2.1 (SEM) v. 34.1 +/2.5 in the controls), and it was attributable to a mucosal damage in the upper small intestine, suggesting that this played a primary role in the high faecal sterol loss. However, the influx of endogenous cholesterol into the gut had increased, so that in absolute terms the absorption of cholesterol was low only inconsistently. The gluten-free diet caused the opposite changes in the absorption percentage and influx of cholesterol into the gut, while the amount of cholesterol absorbed was only insignificantly increased. Serum cholesterol was significantly correlated with the cholesterol absorbed (r = 0.36; P less than 0.01), faecal endogenous steroids (r = -0.30; P less than 0.05), and cholesterol synthesis (r = -0.29; P less than 0.05). Furthermore, the rise in serum cholesterol during the gluten-free diet correlated negatively with the changes in cholesterol (r = -0.55; P less than 0.05) and bile acid (r = -0.77; P less than 0.01) synthesis. These associations and the lack of correlations between the amounts of cholesterol absorbed and synthesized suggest that the serum cholesterol level and regulation of cholesterol synthesis are interrelated in coeliac disease.

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breastfeeding Scand J Gastroenterol. 1998 Nov;33(11):1186-92. Presence of high levels of non-degraded gliadin in breast milk from healthy mothers. Chirdo FG, Rumbo M, Anon MC, Fossati CA.

Center for the Investigation and Development of Cryotechnology of Foods, Dept. of Immunology, School of Exact Sciences, UNLP, La Plata, Argentina.

BACKGROUND: Secretion of dietary antigens into breast milk has been extensively documented. The presence of these antigens is of relevance because they could be involved in the modulation of the immune response in neonates. The objective of this study is to determine the gliadin concentration in milk, colostrum, and serum samples from healthy lactating mothers on a normal diet. Gliadin levels in milk samples from a group of six mothers after a brief period of gluten restriction were also determined. The molecular weight of secreted gliadins was also analysed. METHODS: Gliadin concentration was determined with a highly sensitive competitive enzyme-linked immunosorbent assay, modified so as to eliminate anti-gliadin antibody

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interference. The level of gliadin/IgA anti-gliadin immune complexes in milk, colostrum, and serum samples was determined. RESULTS: Gliadin was detected in all 49 milk samples. Its concentration varied between 5 and 1200 ng/ml (mean, 178 ng/ml). In colostrum (n = 14) gliadin levels were higher (range, 28-9000 ng/ml; mean, 883 ng/ml), not being detectable in one case. Gliadin was detectable in 14 of 31 serum samples, in which levels were lower than in milk and colostrum samples (mean, 41 ng/ml). Neither a correlation between gliadin levels in milk, colostrum, and serum samples from the same subject nor a relation between gluten intake and gliadin concentration in milk samples from six subjects under a 3-day gluten-free diet could be found. Higher levels of immune complexes were observed in colostrum samples than in milk and serum samples. No correlation was detected between gliadin concentration and the level of immune complexes. The analysis of milk and colostrum samples by immunoblotting showed bands of immunoreactive gliadin presenting Mr similar to those of native proteins from wheat extracts. CONCLUSIONS: Very high levels of gliadin were detected in milk samples from healthy mothers on an unrestricted diet. Gliadin levels were higher than those reported for dietary antigens in other studies. Breast milk contained non-degraded gliadins and gliadin/anti-gliadin IgA immune complexes. Page 343 of 399

J Pediatr Gastroenterol Nutr. 1992 Aug;15(2):159-62.

Gliadin-specific and cow's milk protein-specific IgA in human milk.

Juto P, Holm S.

Department of Clinical Virology, University Hospital, Umea, Sweden.

The presence of gliadin-specific IgA and IgG antibodies in colostrum and serum of 140 newly delivered mothers was assessed by enzyme-linked immunosorbent assay. In addition, cow's milk protein (CMP)-specific IgA was determined in the colostrum samples. From 14 of the mothers longitudinal milk samples were obtained after 1 and 2 months of lactation and from 12 mothers after 3 months. Gliadin-specific IgA was found in 97.1% and gliadin-specific IgG in 9.3% of the colostrum samples. Gliadin-specific IgA was detected in mature samples but at significantly lower levels after 1, 2, and 3 months of lactation (p less than 0.01) as compared with colostrum. Gliadin-specific IgA was found in 2.8% of the serum samples and gliadin-specific IgG in 40%;

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however, the levels of both isotypes were low. CMP-specific IgA was found in 78.1% of the colostrum samples. It is concluded that IgA antibodies to two common food proteins are frequently found in human milk and that food-specific IgA present in milk may play a role in adapting the infant's immune reactions to food antigens in the gut.

Clin Exp Immunol. 1998 Jun;112(3):453-8.

Detection and characterization of antibodies specific to food antigens (gliadin, ovalbumin and beta-lactoglobulin) in human serum, saliva, colostrum and milk.

Rumbo M, Chirdo FG, Anon MC, Fossati CA.

Centro de Investigacion y Desarrollo en Criotecnologia de Alimentos (CONICET-UNLP), La Plata, Argentina.

Antibodies against food antigens are usually produced in healthy people. This humoral response can be detected both in serum and secretions. The characterization of this response can be useful for a better understanding of food-related immunological alterations. In this study, IgA and IgG

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antibodies specific to ovalbumin, beta-lactoglobulin or gliadin were measured in serum, saliva, colostrum and milk from 40 healthy breast-feeding women. Specific IgA and IgG to the three antigens were measured by indirect ELISA. Specific IgG levels were highest in serum and very low in the other biological fluids. No correlation between the IgG specific to the different antigens was found. Specific IgA reactivity was found in all the samples analysed. Levels observed were higher in colostrum and milk than in serum and saliva. In spite of being three different unrelated food antigens, a correlation between the levels of specific IgA was found in saliva, colostrum and milk samples of all subjects studied. The specificity of IgA anti-gliadin antibodies from serum, saliva and colostrum was analysed by immunoblotting of SDS-PAGE-separated wheat proteins. Each sample presented a unique pattern of recognition. No common pattern of recognition was found either among the same biological fluids of the different subjects tested, or among the different samples--either serum, colostrum or saliva--of the same individual. Different degrees of specificity to wheat proteins among IgA from colostrum, saliva or serum were observed, suggesting that the local IgA-producing populations are functionally different in the different tissues of the organism.

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Acta Paediatr Scand. 1987 May;76(3):453-6.

Passage of gliadin into human breast milk.

Troncone R, Scarcella A, Donatiello A, Cannataro P, Tarabuso A, Auricchio S.

Samples of breast milk were taken from 53 women following the ingestion of 20 g of gluten. The samples were analysed for the presence of gliadin by a double-antibody sandwich enzyme immunoassay. Gliadin (5-95 ng/ml) was detected in 54/80 samples collected at various stages of lactation. Maximum levels in milk were found 2-4 hours after ingestion; gliadin could not be detected in serum. The transfer of gliadin from mother to infant might be critical for the development of an appropriate specific immune response to gliadin later in life.

J Int Med Res. 2000 Sep-Oct;28(5):234-40.

Gliadin-specific IgA antibodies in breast milk.

Ozkan T, Ozeke T, Meral A. Page 347 of 399

Department of Paediatric Gastroenterology, University of Uludag, Medical School, Gorukle-Bursa, Turkey. [email protected]

Breast-feeding helps to protect against coeliac disease because of the presence of antigliadin-IgA antibodies (AGA-IgA) in breast milk. The aim of this study was to assess the concentrations of AGA-IgA in breast milk during lactation, and whether these concentrations vary with the socioeconomic status of the women. Samples of serum for determination of IgA albumin and AGA-IgA, and samples of breast-milk for AGA-IgA were collected from 105 healthy mothers (aged 17 - 36 years). Women were divided into two groups: group 1 were of low and group 2 were of high socioeconomic status. No differences were observed between the study parameters in the two groups. Serum AGA-IgA in both groups was, however, significantly lower than that in colostrum. AGA-IgA concentrations in both groups gradually decreased during 45 days of lactation; the difference between colostrum and the samples taken at days 10 and 30 - 45 of lactation was significant. The encouragement of sufficient and long-term (e.g. 4 - 6 months) breast-feeding seems likely to be beneficial in preventing coeliac disease.

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Arerugi. 1989 Apr;38(4):342-51.

[Allergological study of breast feeding, ovalbumin and specific IgG, IgM and IgA antibodies to ovalbumin in human milk]

Ogura H, Ogura Y, Tomoda T, Zushi N, Kurashige T.

Ovalbumin (OA) and specific antibodies to OA were evaluated by ELISA in 92 colostrum, 366 mature milk and 12 cord blood samples. Anti-OA IgG antibody titers in colostrum were lower than those in cord blood and were not detectable in several samples. Anti-OA IgM antibody titers in colostrum were comparatively high and decreased on the days following postpartum. Anti-OA IgA antibody titers were the highest in the colostrum and decreased on the following days, but remained constant in mature milk. On the other hand, OA was detected in 27.2% of colostrum and 17.2% of mature milk samples, in concentrations from 0.5-59.0 ng/ml. In mature milk, the positive rates of OA were significantly elevated by egg ingestion by the mothers. OA in mature milk from allergic mothers tended to be more readily detectable than that from non-allergic mothers. These results suggest that avoidance of the specific food antigens by

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mothers is important for therapy and prevention on allergic disease in their breastfed infants.

J Clin Lab Immunol. 1983 Dec;12(4):175-8.

Distribution of serum antibodies to wheat gliadin and bovine milk in atopic and non-atopic healthy adults.

Barnes RM, Barton PG, Doig JE, Finn R, Harvey MM, Johnson PM.

Sera from 262 blood donors were tested against wheat gliadin and bovine milk antigens employing an ELISA system. 9.2% of the sera clearly contained antibodies, predominantly IgG but also including IgA and occasional IgM, reactive with either gliadin (11/262) or milk (13/262). There was no overlap between the gliadin and milk groups, and only one of these sera was also IgE-RAST-positive against wheat or milk. Five of 48 sera with raised IgE levels (greater than or equal to 100 iu/ml) were ELISA-positive against either gliadin or milk, a frequency comparable with that overall in this normal adult population. Six of these 48 sera with raised IgE levels were

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IgE-RAST-positive against wheat or milk, of which only one was ELISA-positive. These results have indicated that nearly 10% of normal adults have serum IgG/A/M antibodies to milk or gliadin, but that this population is separate from individuals (2.3%) who may be IgE-RAST-positive to the same dietary antigens.

free Pediatr Res. 2000 Jan;47(1):157-62.

Cytokines in breast milk from allergic and nonallergic mothers.

Bottcher MF, Jenmalm MC, Garofalo RP, Bjorksten B.

Department of Health and Environment, Faculty of Health Sciences, Linkoping, Sweden.

The allergy-preventing effect of breast-feeding remains controversial, possibly because of individual variations in the composition of the breast milk. The aim of this study was to investigate the concentrations of cytokines involved in allergic reactions and IgA antibody production in breast milk from allergic and nonallergic mothers. The cytokine concentrations were determined Page 351 of 399

in colostrum and 1-mo. milk samples from 24 mothers with, and 25 mothers without, atopic symptoms, using commercial ELISA kits. The immunosuppressive cytokine transforming growth factor-beta was predominant and was detectable in all milk samples. IL-6 was detected in the majority of colostral and mature milk samples, whereas the other cytokines were less commonly detected. The concentrations of IL-6, IL-10, and transforming growth factor-beta, which are all involved in IgA synthesis, correlated with each other and with total IgA concentrations in colostrum. The concentrations of IL-4 were higher in colostrum from allergic than nonallergic mothers, and similar trends were seen for IL-5 and IL-13. In conclusion, transforming growth factor-beta and IL-6 were the predominant cytokines in human milk. The correlation between the concentrations of cytokines involved in IgA synthesis, i.e. IL-10, IL-6, and transforming growth factor-beta, may explain the stimulatory effect on IgA production in breast-fed babies. Varying concentrations of IL-4, IL-5, and IL-13 may explain some of the controversy regarding the possible allergy-preventive effect of breast-feeding.

Diabetes. 2002 Jan;51(1):73-8. Page 352 of 399

Oral exposure to diabetes-promoting food or immunomodulators in neonates alters gut cytokines and diabetes.

Scott FW, Rowsell P, Wang GS, Burghardt K, Kolb H, Flohe S.

Molecular Medicine Program, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada. [email protected]

Disease development in diabetes-prone BB rats is modified by the type of diet fed after weaning. The aim of this investigation was to determine whether exposure during the first week of life to antigens from a known diabetes-promoting diet (NIH-07) could modify diabetes incidence and, if so, to what extent this occurs via alterations in systemic T-cell reactivity, gut cytokines, or islet infiltration. Diabetes-prone BB (BBdp) rats were hand-fed twice daily between age 4 and 7 days with vehicle, a hydrolyzed casein (HC)-based infant formula, Pregestimil (PG), PG + cereal-based NIH-07 diet, PG + lipopolysaccharides (LPS) or PG + LPS + silica. After weaning, they were fed either an NIH-07 diet or a semipurified HC (diabetesretardant) diet until 150 days. In separate studies, 5-day-old BBdp rat pups were administered the aforementioned treatments, and expression of intestinal mRNA for gamma-interferon (IFN-gamma) or transforming growth factor-beta (TGF-beta) was quantified using reverse Page 353 of 399

transcriptase-polymerase chain reaction. The effect of early oral treatment with NIH-07 or PG on systemic T-cell reactivity was evaluated using footpad swelling delayed-type hypersensitivity (DTH) and the popliteal lymph node assay. Oral exposure of neonates to a complex mixture of antigens from the diabetes-promoting diet delayed onset of diabetes (79 vs. 88 days) and prevented disease in approximately one-third of animals. A similar protective effect was seen for neonatal exposure to wheat gluten in animals subsequently weaned onto a semipurified wheat gluten diet. By contrast, LPS-treated neonates displayed more severe insulitis and developed diabetes at an increased rate, which was significantly suppressed by coadministration of silica particles. The protective effect of early exposure to diabetogenic diets was not associated with significant reduction of islet infiltration, and there was no impact on the DTH response to food antigens. However, whereas diabetes-resistant BBc rats developed systemic tolerance to NIH-07 antigens fed chronically, BBdp rats did not. The lack of effect of the early oral antigen regimen on the DTH reaction in the footpad, a classic Th1-mediated reaction, suggests little effect on systemic T-cell reactivity. However, local effects were observed in the small intestine. Oral exposure to diabetes-promoting food antigens or LPS downregulated the Th1 cytokine IFN-gamma and decreased the IFN-gamma/TGF-beta ratio. Thus, oral exposure to Page 354 of 399

diabetes-promoting food antigens and immune modulators in neonates can modify diabetes expression in association with changes in local cytokine balance in the gut.

Diabetes. 1997 Apr;46(4):589-98.

Potential mechanisms by which certain foods promote or inhibit the development of spontaneous diabetes in BB rats: dose, timing, early effect on islet area, and switch in infiltrate from Th1 to Th2 cells.

Scott FW, Cloutier HE, Kleemann R, Woerz-Pagenstert U, Rowsell P, Modler HW, Kolb H.

Nutrition Research Division, Health Canada, Sir Frederick Banting Research Centre, Ottawa,Ontario. [email protected]

Certain diets can have major effects on the development of IDDM in DP-BB rats, but data are scant on the timing, dose, and mechanisms involved. We therefore determined the dose response, timing, and duration of exposure required to induce diabetes, and characterized the effects of nutritionally adequate diets with widely different diabetogenicity on the pancreatic islet area and cytokines. DP-BB rats were fed a diabetogenic, cereal-based, NIH-07 (NIH) diet or a Page 355 of 399

protective, casein or hydrolyzed casein (HC)-based, semipurified diet. Rats were fed from weaning to 50 or 100 days with the HC diet and then switched to the NIH diet, or fed the NIH diet from weaning to 50 days and switched to the HC diet. Pancreas histology and diabetes outcome were determined. Semiquantitative morphometric analyses of hematoxylin and eosin-stained sections of pancreas from 41-day-old rats were also carried out. Dietinduced effects on pancreatic cytokine levels were measured at 70 days using reverse transcriptase-polymerase chain reaction analysis of gamma-interferon (IFNgamma), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-beta). Longterm daily exposure, particularly around the beginning of puberty to late adolescence (50-100 days), was important for development of diabetes. DP-BB rats could be rescued from diabetes development by feeding them a low-diabetogen HC diet as late as 50 days. Diabetes frequency was highest in rats fed 70% and 100% NIH diets. By age 41 days, before classic insulitis, the islet area in HC-fed DP-BB rats was 65% greater than in NIH-fed rats. By 70 days, when mononuclear cells were visible in the islets of most NIH-fed, but not HC-fed rats, the more pronounced inflammatory process in NIH-fed rats was associated with a Th1 cytokine pattern (high IFN-gamma and low IL-10 and TGF-beta), whereas the pancreases of HC-fed rats showed Page 356 of 399

fewer infiltrating cells, low levels of IFN-gamma, and high levels of TGF-beta, typical of a Th2 cytokine pattern. Thus dietary modification can occur as late as puberty. Further, long-term exposure to sufficient amounts of food diabetogens between 50 and 100 days was required for maximum diabetes induction. The islet area was modified by diet before signs of classic insulitis. Pancreatic inflammation in NIH-fed animals is a Th1-dependent phenomenon. The HC diet inhibited insulitis and was associated with a Th2 cytokine pattern in the pancreas, protecting diabetes-prone rats from developing diabetes.

J Allergy Clin Immunol. 1999 Dec;104(6):1251-7.

Transforming growth factor-beta in breast milk: a potential regulator of atopic disease at an early age.

Kalliomaki M, Ouwehand A, Arvilommi H, Kero P, Isolauri E.

Departments of Paediatrics and Biochemistry and Food Chemistry, University of Turku, Finland.

BACKGROUND: According to data from animal and in vitro studies, transforming growth Page 357 of 399

factor-beta (TGF-beta) has a crucial effect on 2 essential parts of the mucosal immune system: IgA production and oral tolerance induction. OBJECTIVE: We sought to ascertain whether TGF-beta in breast milk is associated with specific IgA production and atopic disease in human subjects. METHODS: Forty-seven infants with several atopic family members were followed during their first year of life. The concentrations of TGF-beta1 and TGF-beta2 in maternal colostrum, mature milk, and the infants' sera were determined. The enzyme-linked immunospot assay was used to assess the infants' specific IgA production in response to betalactoglobulin, casein, gliadin, and ovalbumin. RESULTS: At 12 months, atopic dermatitis was confirmed in 29 of 47 infants; in 11, atopic disease had begun during exclusive breast-feeding (preweaning onset), whereas in 18 the disease manifested itself after weaning (postweaning onset). The concentrations of both TGF-beta1 and TGF-beta2 were higher in maternal colostrum, but not in mature milk and infants' serum, in infants with postweaning-onset atopic disease compared with those with preweaning-onset disease (P =.0008 and P =. 015, respectively). The concentration of TGF-beta2 was, and that of TGF-beta1 tended to be, higher in the colostrum of mothers whose infants had specific IgA-secreting cells at 3 months in response to at least one of the dietary

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antigens tested compared with those who did not have such cells (P =.048 and P =.076, respectively). CONCLUSION: TGF-beta in colostrum may prevent the development of atopic disease during exclusive breast-feeding and promote specific IgA production in human subjects.

Cytokine. 2003 Feb 7;21(3):149-54.

A wheat-based, diabetes-promoting diet induces a Th1-type cytokine bias in the gut of NOD mice.

Flohe SB, Wasmuth HE, Kerad JB, Beales PE, Pozzilli P, Elliott RB, Hill JP, Scott FW, Kolb H.

German Diabetes Research Institute, Auf'm Hennekamp 65, Dusseldorf 40225, Germany.

Dietary antigens are candidate environmental factors in the pathogenesis of type 1 diabetes. In the non-obese diabetic (NOD) mouse, an animal model of type 1 diabetes, cerealbased diets promote disease development, whereas the diets based on hydrolysed proteins or non-diabetogenic proteins are protective. The hypothesis that diabetogenic diets modulate the cytokine balance in the gut was tested. NOD mice were fed with NTP-2000 (mainly a Page 359 of 399

wheat-based milk-free diet) or Prosobee (a semi-purified hypoallergenic diet based on soy protein isolate) or Prosobee plus casein (milk protein fraction). The mRNA levels of IFN-gamma, IL-10, TNF-alpha, TGF-beta, and inducible NO synthase in the small intestine and the Peyer's patches were determined by semi-quantitative RT-PCR. Mice fed on the cereal-based NTP-2000 diet expressed higher levels of the Th1-type and proinflammatory markers IFN-gamma, TNF-alpha, and inducible NO synthase mRNA compared to the Prosobee-fed animals. The expression of the counterregulatory cytokines IL-10 and TGF-beta was unaffected. This resulted in a significant bias of the intestinal cytokine balance towards T helper cell type 1 after feeding NTP-2000. The cytokine mRNA levels in the gutassociated Peyer's patches were not affected. Thus, modulation of gut immunoreactivity by diet may contribute to disease development in NOD mice.

celiac Cholecystokinin

Gastroenterology. 1985 Feb;88(2):391-6. Page 360 of 399

Defective gallbladder emptying and cholecystokinin release in celiac disease. Reversal by gluten-free diet.

Maton PN, Selden AC, Fitzpatrick ML, Chadwick VS.

Normal volunteers (n = 6), patients with untreated celiac disease and subtotal villous atrophy (n = 6), patients with nonresponsive celiac disease (n = 2), and patients with celiac disease on a gluten-free diet with a virtually normal biopsy specimen (n = 6) drank a liquid fat meal after an overnight fast. Gallbladder emptying was monitored by using 99mTc-eHIDA, and blood samples were taken for cholecystokinin estimation by radioimmunoassay after highperformance liquid chromatography. The half-times of gallbladder emptying were 20.4 +/- 2.9 min (mean +/- SEM) for normals and 22.1 +/- 2.8 min in treated patients with celiac disease (NS). In patients with untreated celiac disease half-times were 154.3 +/- 10.3 min (p less than 0.02 vs. normals and treated patients with celiac disease), and in 2 nonresponsive patients, half-times were 40.7 and 37.3 min. Integrated plasma cholecystokinin responses were 473 +/- 87 and 436 +/137 pmol X L-1 X 30 min-1 in normals and treated patients with celiac disease (NS). In untreated patients with celiac disease values were 16 +/- 9 pmol X L-1 X 30 min-1 (p less than 0.001 vs. normals Page 361 of 399

and treated patients with celiac disease), and in nonresponsive patients values were 442 and 322 pmol X L-1 X 30 min-1. In 2 patients studied before and during gluten-free diet half-times for gallbladder emptying changed from 168.9 and 302.4 min to 20.1 and 23.4 min, and cholecystokinin responses changed from 0 and 45 to 623 and 298 pmol X L-1 X 30 min-1. Cholecystokinin immunoreactivity cochromatographing with cholecystokininoctapeptide was responsible for 50%-60% of circulating cholecystokinin in normals and in treated patients but the small amount of cholecystokinin that was released in untreated patients with celiac disease cochromatographed with cholecystokinin-33/39. We conclude that there is a reversible defect of gallbladder emptying and cholecystokinin release in celiac disease.

J Radiol. 1984 Mar;65(3):133-6.

[Gallbladder atony and celiac disease in adults. Radiographic and echographic study of 15 cases]

Delamarre J, Capron JP, Joly JP, Remond A, Audebert M, Murat JL, Revert R, Trinez G.

Gallbladder emptying was evaluated in 15 adult celiac disease patients by oral cholecystography Page 362 of 399

or ultrasonography, after fatty meal or cholecystokinin stimulation. Gallbladder inertia was found in 13 cases. Our study agrees with previously reported results; however it is the first one in which this abnormality was demonstrated by ultrasonography. Our findings may suggest that gallbladder inertia is due to duodenal release of an inactive endogenous cholecystokinin. Control studies demonstrates that gallbladder inertia is reversible after gluten-free diet, recurs with relapse, and thus represents a true celiac disease sign, and not an associated condition. Finally, our cases suggest that gallbladder inertia may be radiologically evident before clinical features of malabsorption become apparent. Awareness of this possibility may persuade the radiologist to research in this condition an occult celiac disease.

Dtsch Med Wochenschr. 1985 Feb 15;110(7):259-64.

[Pancreatic secretion in domestic sprue]

Otte M, Thurmayr GR, Dageforde J, Thurmayr R, Forell MM.

Pancreatic function was determined (using the secretin-pancreozymin test) before the use of Page 363 of 399

gluten-free diet in 22 patients with endemic (celiac) sprue. Water and bicarbonate secretion were within normal limits, if anything there was a trend to high-normal values. Remarkable and apparently characteristic for celiac sprue was the only slight contraction of the gallbladder after intravenous injection of submaximal doses of cholecystokinin-pancreozymin (CCK). Secretion of the 3 enzymes amylase, lipase and trypsin was decreased in about one third of cases, the difference relating both to the concentrations and the amount secreted, compared with normal control values was significant (P greater than 0.01). But in no case was the reduced enzyme secretion so marked that one would expect maldigestion. Multivariate non-linear discriminance analysis demonstrated that pancreatic secretion in sprue is quite distinct from that in healthy subjects and those with chronic pancreatitis. It is assumed that there is a pattern of exocrine pancreatic secretion typical for sprue.

Scand J Gastroenterol. 2001 Oct;36(10):1044-8.

Gastric emptying of realistic meals with and without gluten in patients with coeliac disease. Effect of jejunal mucosal recovery.

Page 364 of 399

Benini L, Sembenini C, Salandini L, Dall'O E, Bonfante F, Vantini I.

Gastroenterology, Rehabilitation Hospital of Valeggio sM, University of Verona, Italy. [email protected]

BACKGROUND: Few data are available on disturbed gastric emptying in patients with coeliac disease. The aims of the study were to investigate (a) the presence of delayed gastric emptying: (b) the acute effect on gastric emptying of gliadin; and (c) the effect of jejunal recovery on gastric emptying of meals with or without gluten in such patients. METHODS: We measured gastric emptying of two meals in 16 patients with coeliac disease; one meal contained gliadin. Results were compared with those obtained in 24 controls. In 12 patients, both measurements were repeated after mucosal recovery. Statistical analysis was performed using the analysis of variance for repeated measurements and Student's t test. Mean +/- 1 s(mean) (standard error of the mean) are shown. RESULTS: No difference was found in fasting and in maximal antral sections after the two meals. On entry, gastric emptying was significantly (P < 0.001) delayed compared to controls both after the meal containing gluten (326.9 +/- 12.4 min versus controls 213.5 +/11.5) and after the gluten-free meal (315.3 +/- 16.7 min). After jejunal recovery, emptying of the

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meal containing gluten remained unchanged (337 +/- 18.9 min), whereas emptying of the gluten-free meal was significantly shortened (280.6 +/- 10.5 min; P < 0.001). CONCLUSIONS: In coeliac disease there is an impairment of gastric emptying which is at least partially reversible. This suggests either an immunological disorder or that unabsorbed meal constituents are responsible for an ileal-brake effect.

Acta Paediatr. 2000 Aug;89(8):921-5.

Gastric emptying of solids is delayed in celiac disease and normalizes after gluten withdrawal.

Perri F, Pastore M, Zicolella A, Annese V, Quitadamo M, Andriulli A.

Gastroenterology, Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy. [email protected]

Several gastrointestinal motor abnormalities have been detected in patients with celiac disease, but it is unclear whether they are able to influence the gastric emptying rate. The aim of this work was to evaluate the gastric emptying rate of solids in children with celiac disease before and after Page 366 of 399

a gluten-free diet. Nine children with celiac disease and nine healthy controls (age range 4-16 y) underwent a 13C-octanoic acid breath test to measure gastric emptying. Half emptying time (t1/2) and lag phase (t(lag)) were calculated. After 6 mo of a gluten-free diet, all celiac children underwent a repeat 13C-octanoic acid breath test. The gastric motility parameters, t1/2 and t(lag), were significantly longer in patients than in controls. No significant correlation between abnormal gastric emptying and specific symptom patterns or severity of histological damage was found. On a gluten-free diet, the gastric emptying rate normalized in all celiac patients. This finding supports the hypothesis that gluten-driven mucosal inflammation might determine motor abnormalities by affecting smooth muscle contractility or impairing the release of neurotransmitters. Alternatively, nutrient malabsorption might determine significant changes in intraluminal milieu, which, in turn, may affect intestinal motor functions. CONCLUSION: patients affected by celiac disease have a markedly delayed gastric emptying of solids, which returns to normal after gluten withdrawal.

Regul Pept. 2002 Dec 31;110(1):55-63.

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Persistent decreased plasma cholecystokinin levels in celiac patients under gluten-free diet: respective roles of histological changes and nutrient hydrolysis.

Deprez P, Sempoux C, Van Beers BE, Jouret A, Robert A, Rahier J, Geubel A, Pauwels S, Mainguet P.

Department of Gastroenterology, Cliniques Universitaires St-Luc, Catholic University of Louvain, Av. Hippocrate 10, B-1200, Brussels, Belgium. [email protected]

Celiac disease is associated with impaired cholecystokinin (CCK) release. The mechanism by which CCK release is impaired is poorly understood and seems to be related to the mucosal atrophy or to decreased stimulation due to reduced intraduodenal nutrient hydrolysis. The aims of our study were to evaluate basal and postprandial CCK in celiac patients presenting with distinctive types of mucosal lesions (normal, infiltrative and atrophic), and to study the role of protein hydrolysis on CCK release. Plasma CCK was measured in 20 celiac patients (normal mucosa: n=6; infiltrative type: n=6; atrophic type=8) and 9 controls, before and after ingestion of a polymeric or a semi-elemental meal. Significant decreases in basal CCK plasma (B 0.6 [95% CI, 0.3-1.3] pmol/l; p