Clinical Endocrinology (1999) 50, 267–270

Case report

267q 1999 Blackwell Science Ltd

Apparent cure of Graves-Basedow disease after siblingallogeneic bone marrow transplantation

Santiago Dı´ez*, Helena Banias†, Jose´ L. Dıez-Martin†,Montserrat Briz†, Janvier Estrado* and BalbinoBarcelo *Departments of *Endocrinology and †Haematology,Clınica Puerta de Hierro, Universidad Autonioma,Madrid, Spain

(Received 19 December 1997; returned for revision 19 January1998; finally revised 17 April 1998; accepted 11 May 1998)

Summary

Evidence that allogeneic bone marrow transplanta-tion (BMT) can cure or alter the course of intractableautoimmune diseases comes from both extensiveexperimental work in animal models and anecdotalcase reports in humans.

We describe a female patient diagnosed as havingsevere aplastic anaemia (SAA), hyperthyroidism andophthalmopathy of Graves-Basedow disease whoreceived a BMT from her histocompatible sister.

Fifty-three months after BMT, complete remissionof hyperthyroidism and ocular signs persists. TheSAA is cured and she is free of any chronic graft-versus-host disease (GVHD).

In the early post-BMT period, PCR analysis of bonemarrow and peripheral blood cells confirmed a com-plete chimerism of donor origin. Thus, it is plausible toattribute the resolution of the patient’s thyroid hyper-function and opththalmopathy to the replacement ofthe host immune system.

Graves-Basedow disease is the most frequent cause ofhyperthyroidism and is associated with a typical ophthalmo-pathy. This organ-specific process is characterized by thepresence of thyroid stimulating immunoglobulins of IgG classwhich, binding to the TSH receptor, induce thyroid hyper-function. Its pathogenesis apparently begins with the activationof self-reactive T helper lymphocytes, with particular thyroidantigen specificity (Dayan & Daniels, 1996), leading, therefore,to the development of an autoimmune disorder (AD). Inaddition, the pathogenesis of the ophthalmopathy, alsoimmunologically mediated, is poorly understood.

Experimental work in animal models has shown thatnumerous ADs can be transferred to healthy animal recipientsby allogeneic bone marrow transplantation (BMT), particularlyafter conditioning therapy with total body irradiation. Likewise,BMT from an AD resistant animal strain can prevent somespontaneous and induced ADs (Van Gelder & Van Bekkum,1995). In humans, the transfer of autoimmune thrombocyto-penic purpura (Minchintonet al., 1982), glomerulonephritis(Haslamet al., 1993), myasthenia gravis (Haslamet al., 1993),Graves-Basedow disease (Aldouriet al., 1990; Hollandet al.,1991; Thomsonet al., 1995) and autoimmune hypothyroidism(Aldouri et al., 1990; Wyattet al., 1990) from BMT donors torecipients who underwent BMT to treat their haematologicaldiseases has been reported. Conversely, several patients withhaematological disorders and pre-existing AD, such asrheumatoid arthritis (Lowenthalet al., 1993), psoriasis orulcerative colitis (Liu Yin & Jowitt, 1992), apparently achievedcure of AD after a BMT. The above mentioned reports of thetransfer of Graves-Basedow disease by BMT support thehaemopoietic origin of the donor thyroid stimulating factors.However, to our knowledge, there have been no reports ofremission of autoimmune hyperthyroidism in a BMT recipient.

We report here a patient with Graves-Basedow disease whoachieved clinical and biochemical resolution of her hyper-thyroidism and correction of her ophthalmopathy following aBMT performed to treat concomitant severe aplastic anaemia(SAA).

Case report

Recipient

In May 1993, a 30 year-old woman was diagnosed as havingGraves-Basedow disease. Six months earlier, she had startedwith asthenia, nervousness, hyperhidrosis, tremor, ocularchanges and goitre. Physical examination revealed a palpablehypervascularized thyroid gland accompanied by a hyper-dynamic cardiovascular state and excessively warm and moistskin. In addition to eyelid retraction, the patient had proptosisand marked periorbital oedema without conjunctival swelling.The diagnosis of hyperthyroidism was confirmed with serumFT4 levels of 42·6 pmol/l and undetectable TSH. Autoimmunitystudies disclosed a TSH-binding inhibition (TBI) of 18·1 mU/ml, a microsomal antibody level of 765 IU/ml and athyroglobulin antibody level of 164 IU/ml (Table 1).

Two months before admission, she developed epistaxis,

Correspondence: Dr. Balbino Barcelo´, Servicio de Endocrinologı´a,Clınica Puerta de Hierro, 28035 Madrid, Spain. Fax:þ34 91 3160398.

gingival bleeding and subconjunctival hemorrhage. Peripheralblood counts showed a white blood cell count of 6·1×109/l withneutrophils<0·5×109/l (6% neutrophils, 91% lymphocytes, 3%monocytes), haemoglobin of 7·4/dl, a platelet count of 18×109/land 0·6% uncorrected reticulocytes. A bone marrow biopsyconfirmed marrow aplasia and the cytogenetic analysis revealedonly 46,XX metaphases. She was diagnosed as having SAA.The diagnoses of Graves-Basedow disease and SAA wereconfirmed in May 1993. Their clinical onsets had taken placesix and two months earlier, respectively. The two diseasescoexisted for two months until BMT was performed in June1993.

Sibling donor

The patient’s sister, aged 27 years, had no history of thyroiddisease. In June 1993, her thyroid function test was normal (FT4

18·73 pmol/l and TSH 1·1 mU/l) and her thyroid antibodieswere within normal limits (antimicrosomal antibodies, 192 IU/mland antithyroglobulin, 65 IU/ml). Her TBI was found to beelevated (17·9 mU/ml) despite absence of hyperthyroidism andophthalmopathy.

Allogeneic bone marrow transplantation

The patient received an unmanipulated BMT from her HLA-identical sister (A2, 23; B61, 44; BW6, 4; DR7, 11/DR52, 53/DQ2, 7) in June 1993. Pre-BMT conditioning consisted ofcyclophosphamide (200 mg/Kg). In addition, methotrexate and

cyclosporin A were given for graft-versus-host disease (GVHD)prophylaxis; the plasma cyclosporin A level was maintainedbetween 100–250mg/l until administration was discontinued 6months post-BMT. Hyperthyroidism was managed withpropanolol (20 mg/6 h); the thionamides were avoided owingto their possible myelotoxic effects.

Neutrophil and platelet engraftment were reached at daysþ21 andþ23 post-BMT, respectively. At dayþ20 post-BMT,the patient developed acute GVHD grade II involving the skinand the gastrointestinal tract. This was corrected withmethylprednisolone pulse therapy. At dayþ50, she wasdischarged, free of complications, with stable blood counts,and PCR analysis showed complete donor chimerism.

At the present time, four years and five months post-BMT,she is asymptomatic and remains in complete haematologicalremission and complete donor chimerism, being totally free ofchronic GVHD.

Material and methods

Measurement of free T4 (FT4) was performed by a competitiveimmunoassay (Amerlite MAB FT4 Assay, Amersham UK;normal range 11·79–22·27 pmol/l). TSH was determined byimmunometric assay (Amerlite TSH-30 Ultrasensitive Assay,Amersham UK; normal range 0·3–4·2 mU/l). Thyroglobulinand microsomal antibodies were measured by an enzymeimmunoassay (Immunowell Gembio, San Diego US; normalvalues <250 IU/ml and <300 IU/ml, respectively). Thyroidstimulating autoantibodies were determined by TSH-binding

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Table 1 Thyroid function and autoantibody results before and after BMT*.

Thyroglobulin MicrosomalFT4 TSH antibody antibody TBI

Time of test (pmol/l) (mU/l) (IU/ml) (IU/ml) (mU/ml)

Pre-BMT 42·6 0·00 164 765 18·10Post-BMT0·5 months 52·1 0·00 – – –1·5 months 22·3 0·00 142 475 0·003 months 12·2 0·00 – – 0·005 months 15·6 0·00 78 154 3·807 months 15·0 0·42 – – 0·0012 months 16·9 0·77 1525 0·00 5·9017 months 14·5 0·54 – – 18·9020 months 14·3 0·36 912 97 3·1124 months 19·4 0·42 – – –30 months 13·2 0·30 – – 0·2334 months 14·0 0·96 – – 16·3039 months 17·3 1·18 – – 0·0053 months 15·5 0·38 905 258 4·70Normal range 11·8–22·3 0·3–4·2 <250 <300 <10

inhibition (TBI) from TRAK-Assay (BRAHMS DiagnosticaGmbH, Berlin Germany; normal value<10 mU/ml).

The HLA serological study was performed by micro-lymphocytotoxicity assay with non-commercial plaques (DrVicario, Histocompatibility Centre, Community of Madrid,Spain).

The chromosomal studies were analyzed in nonstimulated24 h bone marrow cultures, after GTG and G-Wright banding.Haematopoietic chimerism was documented by PCR amplifi-cation of hypervariable regions (minisatellite APO-B). Thesensitivity is estimated at around 1%.

Results

Table 1 shows the recipient’s levels of FT4, TSH, antithyroidantibodies and TBI, before and after BMT. Post-BMT weobserved the normalization of both FT4 and TSH, as well as thedevelopment of microsomal antibody and TBI negativity. TSHwas definitely normalized several months after FT4, as usuallyoccurs after the remission of hyperthyroidism.

About one month post-BMT, we noticed the completedisappearance of the ocular signs and later of the goitre.

After the first year post-BMT, the TBI positivity recurredintermittently, and antithyroglobulin antibody titres (negativepre-BMT) increased.

Discussion

The transmission of autoimmune disorders following BMTfrom carrier donors to recipients and the achievement ofremission of AD after BMT from healthy donors have bothbeen reported previously. The present case is, to our knowl-edge, the first report of Graves-Basedow disease remission in apatient who received an allogeneic BMT. The two diseases co-existed clinically for two months before BMT, suggesting thatGraves-Basedow disease can occur in the presence of SAA.This may be due to the fact that in aplastic anaemia there is arelative persistence of lymphocytes in the peripheral blood, asin our patient.

Before BMT, the patient had evident hyperthyroidism andophthalmopathy, with high TBI and microsomal antibodylevels, constituting a classical case of Graves-Basedow disease.After BMT, the thyroid function normalized soon after, goitrediminished, the patient became TBI and microsomal antibodynegative, and her ophthalmopathy vanished. Therefore, it canbe argued that the long-lasting remission of hyperthyroidismand ophthalmopathy achieved in this patient could be caused bythe replacement of her lymphohaematopoietic system. This isconfirmed by studies which revealed complete donor lympho-haematopoietic chimerism in the recipient.

The TBI levels of the patient normalized soon after BMT androse intermittently at 17 and 34 months. This was notaccompanied by evidence of thyroid hyperfunction or ophthal-mopathy. We believe there is a strong possibility that anactivated TBI producing clone was transferred with the bonemarrow, explaining the late post-BMT presence of elevatedTBI levels.

The absence of hyperthyroidism can be explained by the factthat the antibodies against the TSH receptor are polyclonal andfunctionally heterogeneous. In fact, they consist of receptor-stimulating antibody populations (TSAb) and others which,despite binding only to the TSH receptor, compete for TSHbinding and do not stimulate it (TSBAb). These differentantibody populations may coexist in the same patient asdemonstrated by chromatography (Worthingtonet al., 1991;Paschkeet al., 1996).

Our laboratory kit measures only TSH receptor bindinginhibition activity; thus, we were unable to differentiatebetween the recipient who had hyperthyroidism and the donorwho did not, but was equally TBI-positive.

Microsomal antibodies, which are associated with thyroidautoimmunity, normalized by the fifth month post-BMT in thispatient, reflecting the change in thyroid autoimmunity. Themeaning of the marked rise of thyroglobulin antibodies in therecipient after 1 year post-BMT with no expression in the donorremains unclear.

Arguing against the possibility of a spontaneous remissionof Graves-Basedow disease is the exquisite coincidence withthe transplant procedure. The therapeutic response observedin this patient could be due to the high-dose cyclopho-sphamide administered as conditioning regimen or to theeffects of the allogeneic graft on the recipient immunesystem. We consider the latter to be much more likely due tothe long-lasting response of 53 months. Furthermore, theimprovement of the ophthalmopathy could also be ascribed tothe 6 month course of cyclosporin A, as has been reportedelsewhere (Prummelet al., 1988), but the success rate withcyclosporin A was only 22% and the rate of recurrence wasover 50%.

Thus, this case provides strong evidence that allogeneicBMT can lead to long-lasting remission and the eventual cureof Graves-Basedow disease, and supports the hypothesis thatthyroid stimulating immunoglobulins are produced by Blymphocytes from the bone marrow.

Acknowledgements

We are indebted to Dr. Guillermo Maran˜a and Dr. Rafael Fore´sfor their suggestions in the preparation of the manuscript and toMs Martha Messman for her editorial assistance.

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