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Original Paper

Horm Res 1999;51:124127

Prevalence of Coeliac Disease in

Patients with Thyroid Autoimmunity

Rossella Valentinoa Silvia Savastanob Antonio Pasquale Tommasellib Maurizio Doratob

Maria Teresa Scarpittab Marianna Giganteb Maria Micilloc Francesco Paparo c

Emma Petronec Gaetano Lombardib Riccardo Tronconec

aCNR, Experimental Endocrinology and Oncology Center (CEOS), Department of Cellular and Molecular Biology

and Pathology;b

Department of Molecular and Clinical Endocrinology and Oncology, andc

Department of Pediatrics,University Federico II, Naples, Italy

Received: June 19, 1998

Accepted after revision: February 11, 1999

Dr. Rossella ValentinoChair of EndocrinologyUniversity Federico II, via Pansini, 5

ABCFax +41 61 306 12 34

1999 S. Karger AG, Basel03010163/99/05130124$17.50/0

Key Words

Autoimmune thyroid disease W Coeliac disease W Gliadin W

Endomysial antibodies

AbstractThe 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 sub-

jects (3.3%) EmA positivity was found; all underwent

jejunal biopsy. On gluten-free diet an excellent clinical

and histological response was recorded with an im-

provement of hypothyroidism and reduction of the thy-

roxine dosage. Our data suggest a significant high preva-

lence (3.3%) of CD in patients with ATD, in particular with

Hashimotos thyroiditis.

Introduction

Coeliac disease (CD) is a permanent intolerance towheat, rye, barely and possibly oats, sustained by anabnormal immune response to gliadin and corresponding

prolamines of toxic cereals, and responsible of severedamage of the jejunal mucosa [1]. Mostly due to therecent implementation of specific and sensitive serologi-cal tests, the epidemiology of this condition has been radi-cally reconsidered, as well as the clinical presentation of

affected patients. Extraintestinal manifestations of CDhave been increasingly recognized and the associationwith a number of diseases well established [2]. Many dis-eases with an autoimmune pathogenesis are found with ahigher than normal frequency in coeliac patients: amongthese, Addisons disease, pernicious anaemia, autoim-mune thrombocytopenia, sarcoidosis, insulin-dependentdiabetes mellitus and alopecia. The occurrence of thyroiddisorders among patients with CD is also well docu-mented [35], but the exact prevalence of CD amongpatients with autoimmune thyroid diseases is as yet un-clear and must be defined. The aim of this work has been

to evaluate the occurrence of CD in such a population,screening by an antibody test a consecutive series of newlydiagnosed patients.

Patients and Methods

One hundred and fifty adult outpatients, with newly diagnosedautoimmune thyroid disorders, were prospectively enrolled in thestudy from June 1995 to June 1997. There were 136 females (91%)and 14 males (9%), ranging in age between 13 and 48 years. 58 of

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Table 1. FT4, TSH and serum antibodies to thyroglobulin (AbTG), peroxidase (TPO) and endomysium (EmA) in patients with thyroiddisease and associated CD, as meanB SD of three different determinations

Pa-tient

Thyroid diagnosis At diagnosis

AbTG TPO FT4 TSH EmA

After 6 months of gluten-free diet

AbTG TPO FT4 TSH EmA

Hashimotos thyroidits 212B25 2,580B430 7.5B1 9.8B2 ++ 206B32 1,976B88 12B2 1.5B0.3 2 Graves disease 45B12 6,450B230 19.7B4 !0.1 ++ ND ND ND ND ND

3 Hashimotos thyroiditis 225B

32 2,790B

185 6.9B

2 8.9B

2 ++ ND ND ND ND ND4 Hashimotos thyroiditis 450B25 1,230B55 8.2B2 9.1B1 ++ 380B32 1,115B60 10.9B3 1.3B0.5 5 Hashimotos thyroiditis 312B18 1,580B178 7.3B3 7.9B1 ++ 210B25 1,395B118 11.8B2.5 1.1B0.2

ND = Not determined.Normal ranges: AbTG,!100 UI/ml; TPO,!100 UI/ml; FT4, 6.616.8 pg/ml; TSH, 0.33.5 mUI/l; EmA, negative.

Table 2. Clinical features and therapyin patients with thyroid disease andassociated CD, who complied with thegluten-free diet (GFD)

Patient Sex Ageyears

Thyroid disease Therapy atdiagnosis

Therapy after6 months of GFD

F 26 Hashimotos thyroiditis L-T4 125 g/day L-T4 50 g/day

4 F 13 Hashimotos thyroiditisL

-T4 125 g/dayL

-T4 100 g/day5 F 33 Hashimotos thyroiditis L-T4 100 g/day L-T4 50 g/day

L-T4: L-thyroxine.

them (38.6%) had Hashimotos thyroiditis, with clinical signs ofhypothyroidism, diffuse goitre and increased serum thyroid-stimu-lating hormone (TSH), while 18 (12%) had Graves disease, charac-terized by clinical and laboratory evidence of hyperthyroidism (dif-fuse goitre, elevated thyroid hormones and low TSH levels in serum).The remaining 74 patients (49.4%) had multinodular euthyroid

goitre. In all cases high titres of thyroid antiperoxidase antibodies(TPO) were noted, in 69 of them also accompanied by positivity forthyroglobulin antibodies (AbTG). TPO and AbTG were measuredusing commercial radioimmunoassay and immunoradiometric assaykits, respectively (Radim, Pomezia, Roma, Italy).

The patient sera were also screened for IgA class antiendomysiumantibodies (EmA), by indirect immunofluorescence, using humanumbilical cord as substrate [6]. Human umbilical cord was obtainedfrom a pregnant woman at delivery; after excision, the umbilical cordwas cut transversely into small segments, frozen in liquid nitrogen,and kept at 70 C. Then, 5-m umbilical cord sections were cut bycryostat, placed unfixed on slides, and used for EmA detection.Slides were incubated for 30 min with 1:5 and 1:50 diluted patientserum samples. After washing in phosphate-buffered saline 3 times

for 5 min, sections were incubated with FITC anti-human IgA (Beh-ringwerke, Marburg, Germany) for 30 min. The slides were thenwashed 3 times for 5 min, mounted in phosphate-buffered saline (1part) and glycerin (1 part) buffer, and read under a Leitz microscopewith vertical illumination (Xenon XBO 75-W lamp). Selective serumIgA deficiency was excluded in all cases. Subjects with positive EmAunderwent jejunal biopsy, carried out by upper gastrointestinal tractendoscopy.

Results

A total of 150 patients with autoimmune thyroid dis-ease were screened for CD. IgA class EmA were detectedin the serum of 5 patients (3.3%). In all cases the jejunal

biopsy showed total or subtotal villous atrophy, allowingthe diagnosis of CD. Thus, in our cohort of patientsaffected by autoimmune thyroid diseases the prevalenceof CD found was approximately 1:30, 10 times higherthan 1:300 [7, 8] (p 1 0.01 by Fishers exact test).

From a clinical point of view, none of these 5 patients,even in their past history, had gastrointestinal symptomssuggestive of CD. Four of them had Hashimotos thyroid-itis and 1 had Graves disease. In all cases high serum lev-els of both TPO and AbTG could be demonstrated (ta-ble 1). In 1 of them (patient No. 1), further investigations,aimed to diagnose possible other associated autoimmune

disease, allowed the diagnosis of Addisons disease andovarian failure. All patients were prescribed a gluten-freediet, but only 3 accepted. The latter subjects showed anexcellent serological, histological and clinical response in6 months. Their serum endomysial antibodies disap-peared; a control biopsy confirmed mucosal healing; animprovement of symptoms referred to hypothyroidism,as well as a reduction of the L-thyroxine dosage and/or of

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any other hormonal replacement therapy were noted (ta-ble 2). On the contrary, no variations were observed inTPO and AbTG titres (table 1). Only patient No.1, with alonger follow-up of 18 months, revealed a significant de-crease (p ! 0.001) in TPO titre (from 2,580B 430 to 451B 18 U/ml, mean of three different determinations withstandard deviations).

Discussion

The occurrence of thyroid diseases in patients withknown CD and dermatitis herpetiformis is well estab-lished [35, 9, 10]. In different studies [4, 11, 12], from 14to 30% of coeliac patients were reported to be affected bythyroid disease, with serum anti-TPO positivity. Theoccurrence of CD among patients with thyroid diseases isless documented. In a study conducted in patients with

endocrinological problems, 6 out of 32 patients, all withthyroid diseases, showed significant changes of the smallbowel histology, but unresponsive to the gluten-free dietand attributed to autoimmune phenomena [13]. Morerecently, Collin et al. [14], with a series of assays includingmalabsorptive tests, measurement of gliadin and endomy-sial antibodies, have reported a frequency of 4.8% in aseries of 83 patients with autoimmune thyroid disorders.The prevalence found in our study, based on the use ofendomysial antibodies, is very similar. In fact, this latterserological test has certainly a higher sensitivity and speci-ficity for the diagnosis of CD than gliadin antibodies [15];

once excluded, the possibility of a concomitant IgA defi-ciency, another condition also associated with CD, thistool is sufficient for an optimal screening strategy. In fact,also in our series, the positivity of endomysial antibodieswas invariably accompanied to a jejunal histological pic-ture of subtotal villous atrophy. The clinical, serologicaland histological dramatic responses to the gluten-free dietin those subjects, who were compliant with the diet, con-firmed the diagnosis. The prevalence of CD, when thegeneral population is screened for CD, is close to 1:300[7]. In the present study the frequency of CD in patientswith autoimmune thyroid disease was 1:30 and then at

least 10-fold higher. It seems also important to point outthat in our series, patients with Hashimotos thyroiditisseem to have a higher risk of developing CD than patientswith Graves disease and patients with multinodular eu-thyroid goitre, also in the presence of thyroid autoimmu-nity. In this regard it is also interesting to note that CDpatients seem to develop hypothyroidism (Hashimotos?)rather than Graves disease.

The association between CD and autoimmunity ingeneral has been attributed to the fact that coeliac patientswith CD share some HLA antigens with subjects affectedby autoimmune diseases (e.g. B8, DR3, DQw2). Interest-ingly, it has recently been shown that the prevalence ofautoimmune diseases in CD is related to the duration ofexposure to gluten [16], these data suggesting a direct role

of gluten as trigger of the autoimmune process. How glia-din may trigger the production of autoantibodies is still amatter of speculation. In the normal state, B cells specificfor soluble self antigen exist, but they secrete antibodiesonly when help is given by T cells. According to Sollid etal. [17], the appropriate help can be provided by a linkbetween the self antigen and gliadin. Gliadin-reactivehelper T cells in the intestinal mucosa could provide helpfor self antigen-specific B cells. This hypothesis has beenput forward to explain the gluten dependence of antitrans-glutaminase antibodies, but it could explain also the pro-

duction of antithyroid antibodies. The direct role of glia-din as a key factor for the development of autoimmuneresponse emphasizes the need for a prompt diagnosis alsoin absence of manifest coeliac symptoms, with an earlygluten-free diet to prevent autoimmunity.

Nonetheless, it is not less important to diagnose CD inpatients in whom autoimmunity has already developed.Even if both the autoimmune process and the autoantibo-dy levels are reported in the great majority of cases not tobe influenced by the diet [18], the gluten-free diet canavoid a series of other complications, for example osteo-porosis, impaired fertility, anaemia, only to quote some of

them [19]; more importantly it significantly decreases therisk of neoplasia [20]. The experience of our case showsthat, even if the autoimmune process is not reverted com-pletely by the gluten-free diet, the general conditions ofthe patients clearly improve, paralleling the histologicalhealing of the jejunal mucosa; furthermore, a findingwhich has not been emphasized before, these phenomenahave a significant impact on the dose and on the outcomeof the replacement therapy. As a matter of fact, in all ourtreated cases after the diagnosis of CD was made, it hasbeen possible to progressively and significantly reduce thedose of thyroid hormones, with a complete recovery in

thyroid function, associated with a significant and pro-gressive decrease in TPO titre, more related to theinfluence of the gluten-free diet than to the normalizationof TSH plasma levels previously described [21].

In conclusion, our experience confirms the opportuni-ty to screen for CD all patients with autoimmune thyroiddisease [22]. In this regard it must be noted that thescreening by endomysial antibodies detection, in such at-

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risk populations, must be repeated more than once in alifetime, for the possibility of late serum conversion [23].The recognition of a concomitant CD, even if withouttypical gastrointestinal symptoms, allows a more efficientreplacement thyroid therapy.

Acknowledgments

We are grateful to the Gruppo di Studio in Endocrinologia(GSE, Napoli, Italy) and to the Gruppo di Medicina Nucleare(GMN, Napoli, Italy) for financial support.

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