Conversion to Graves disease from Hashimoto thyroiditis: a study of 24 patients

ABSTRACT Objective: The conversion of Hashimoto's thyroiditis (HT) to hyperthyroidism due to thyrotropin receptor antibodies is intriguing and considered rare. The contribution of TSH receptor blocking antibodies (TRAb), which may be stimulators (TSAb) or blockers (TBAb), is suspected. We describe clinical and biological variables in a series of patients switching from Hashimoto's thyroiditis to Grave's disease. Subjects and methods: Retrospective case study of 24 patients with Hashimoto's thyroiditis followed during 48 ± 36 months that developed later Graves' disease (GD). These variables were analysed in the hypo and hyperthyroid phase: age, sex, initial TSH, free triiodothyronine (fT3), free thyroxine (fT4), anti-TPO, TBII antibodies, parietal cell autoantibodies, time between hypo and hyperthyroidism, thyroid volume and levothyroxine doses (LT). Results: In HT, mean TSH was 9.4 ± 26.1 UI/L and levothyroxine treatment was 66.2 ± 30.8 µg/day. The switch to GD was observed 38 ± 45 months after HT diagnosis. As expected, we found significant differences on TSH, FT3, FT4 and TBAb levels. Three out of 14 patients had parietal cell autoantibodies. In two of these three cases there was an Helicobacter pylori infection. There were no significant differences between HT and GD groups with respect to thyroid volume. Conclusions: To our knowledge, large series documenting the conversion of HT to GD are scarce. Although rare, this phenomenon should not be misdiagnosed. Suspicion should be raised whenever thyroxine posology must be tapered down during the follow-up of HT patients. Further immunological and genetic studies are needed to explain this unusual autoimmune change.

Relación entre linfocitos T reguladores (T regs) y anticuerpos anti-receptores de TSH (TRab) y el riesgo de cáncer de tiroides en enfermedad de Graves / Relationship between T regulatory lymphocytes (Tregs) and TSH receptor antibodies (TRab) on risk of thyroid cancer in Graves disease

Durante los últimos años se ha estudiado la relación entre enfermedad de Graves (EG), TSH, TRAb y cáncer de tiroides, existiendo estudios que demuestran mayor prevalencia y agresividad del cáncer de tiroides en pacientes con EG, mientras otros refutan estos hallazgos sugiriendo que serían producto del sesgo de selección. Aquellos estudios que plantean una relación causal entre EG y el desarrollo de cáncer de tiroides, la atribuyen a la presencia de autoanticuerpos TSI, que estimularían el foco de malignidad. Se cree que las citoquinas producidas localmente en pacientes con EG trabajarían en conjunto con los TRAb para determinar la agresividad del cáncer papilar de tiroides en estos pacientes. Dentro de las células reclutadas por el tumor para evadir la respuesta inmune se encuentran los linfocitos Treg, que estarían elevados en paciente con EG, llevando a la disminución de la respuesta inmune y creando un ambiente permisivo para la proliferación celular. Por tratarse de una línea de investigación reciente, no existe consenso sobre el tema y sus implicancias en el tratamiento de los pacientes con EG. La finalidad de este artículo es realizar una revisión de la literatura que exponga y contraste la información disponible a la fecha.

In recent years the relationship between Graves’ disease (GD), TSH, TRAb and thyroid carcinoma has been studied. Research studies show a higher prevalence and aggressiveness of thyroid carcinoma in patients with GD, however other researchers refute these findings suggesting it’s due to selection bias. Increasing evidence suggests a causal relationship between GD and the development of thyroid carcinoma, mainly because of the existence of TSI autoantibodies that could stimulate the focus of malignancy. It is believed that cytokines produced locally in patients with GD work alongside with TRAb regulating the aggressiveness of papillary thyroid carcinoma in these patients. Within the cells recruited by the tumor to elude the immune system we find Treg lymphocytes, which have been found to be increased in patients with GD, leading to a diminished immune response, creating a permissive environment for cell proliferation. Since this is a relatively new line of research, there is no consensus on the subject and its relevance for the treatment of patients with GD. The aim of this article is to show recent literature available on the subject.

Follow-up of a case of subacute thyroiditis with uncommon thyroid 99mTc uptake / Acompanhamento de caso de tiroidite subaguda com absorção incomum de 99mTc pela tiroide

Thyroidal 99mTc uptake in the acute thyrotoxic phase of subacute thyroiditis (SAT) is always inhibited. However, a patient with SAT had signs in the right-side thyroid gland with transient thyrotoxicosis and slightly high 99mTc uptake levels in the right lobe, low 99mTc uptake in the left lobe, and normal overall uptake. Histological examination showed cellular destruction and granulomatous inflammatory changes in the right lobe, with marked interstitial fibrosis in the left lobe. The patient was thyrotrophin-receptor antibody (TRAb) positive. After a short course of prednisolone, SAT-like symptoms and signs improved. TRAb-positivity resolved spontaneously after 22 months, and TSH levels were slightly low for 22 months. Levels then kept normal in the following four years. In conclusion, high 99mTc uptake by the right lobe was due to the combined effects of TRAb and left thyroid gland fibrosis.

A absorção tiroidiana de 99mTc no estado tirotóxico agudo da tireoidite subaguda (SAT) é sempre inibida. Entretanto, um paciente com SAT apresentou sinais na tiroide direita, com tirotoxicose transitória e níveis levemente elevados de 99mTc no lobo direito, baixa absorção de 99mTc no lobo esquerdo e absorção geral normal. O exame histológico mostrou destruição celular e alterações inflamatórias granulomatosas no lobo direito, com fibrose intersticial marcada no lobo esquerdo. O paciente foi positivo para anticorpos antirreceptores da tireotropina (TRAb). Após um curto tratamento com prednisolona, os sintomas e sinais da SAT melhoraram. A positividade para TRAb foi resolvida espontaneamente em 22 meses. Os níveis de TSH permaneceram levemente baixos por 22 meses e, depois, se mantiveram normais nos quatro anos seguintes. Concluiu-se que a alta absorção de 99mTc pelo lobo direito foi devida à combinação entre TRAb e fibrose da tiroide esquerda.

Clinical Applications of TSH Receptor Antibodies in Thyroid Diseases

The cloning and sequencing of thyroid-stimulating hormone (TSH) receptor (TSHR), combined with advances in molecular techniques, have facilitated the understanding of the interaction of the TSHR antibodies (TSHRAbs) with the TSHR at the molecular level and have allowed the delineation of their clinical role. TSHRAbs in vivo are functionally heterogeneous; the stimulating TSHRAbs cause hyperthyroidism and diffuse goiter in patients with Graves' disease, whereas, the blocking TSHRAbs cause hypothyroidism in some patients with autoimmune hypothyroidism and are the cause of transient neonatal hypothyroidism. Measuring TSHRAbs has potential clinical implications in differential diagnosis of Graves' disease, predicting the outcome of Graves' disease after antithyroid drug treatment, and predicting the fetal/neonatal hyperthyroidism or neonatal hypothyroidism. The existence of epitope heterogeneity in a patient, i.e., of stimulating TSHRAbs with epitopes other than on the N-terminal region of the extracellular domain, is significantly associated with favorable long-term clinical response to antithyroid drug treatment. Measuring these subtypes for thyroid-stimulating antibody (TSAb) has potential clinical impli-cations, for example, in predicting responsiveness to treatment in untreated patients with Graves' disease.

Positividade dos anticorpos antitiroidianos na doença de Graves / Positivity of antithyroid antiboidies in Graves' disease

Os auto-anticorpos descritos na doença de Graves säo imunoglobulinas pertencentes à classe IgG que dirigem-se especificamente a certos antígenos tiroidianos, destacando-se entre eles: tireoglobulina (antitireoglobulina), peroxidade tiroidiana (antimicrossomia/antiperoxidade) e receptor do hormônio tireotrófico (TRab). Com o objetivo de avaliar a prevalência dos auto-anticorpos na doença de Graves descompensada, estudamos 46 pacientes virgens de tratamento. Concordante com os dados da literatura, o anticorpo anti-receptor de TSH mostrou-se o melhor marcador da doença de Graves, com 92,4 por cento de positividade

Interet du dosage anticorps antirecepteurs a la tsh

TSH receptor antibodies [TRAB] was performed by binding assay in seventy-seven patients [47 with Graves disease, 32 with other thyroid abnormalities] the sensitivity and specificity of our assay were respectively 81% and 96.5% these resultrs were similar to the results found in medical literature. The association of ophthalmopathy with Graves disease does not increase the sensitivity of the test. In this study we conclude that TRAB assay is of great interest in confirming the diagnosis and in the following of Graves disease

Thyrotoxicosis--treatment by I131 therapy and early prediction of hypothyroidism following this therapy.

This study was undertaken in 68 thyrotoxic patients to assess the predictive value of various post treatment biochemical and immunological tests for early hypothyroidism after I131 therapy and to determine whether pretreatment with carbimazole protects against post I131 therapy hypothyroidism. Early changes observed in serum T3, T4, TSH, thyroid microsomal and thyroglobulin antibody levels were found to be of no predictive value. A sharp increase in TRAb levels around 3 months following I131 therapy indicated that hypothyroidism was likely to occur as this rise reflected a greater degree of thyroid damage. Lower levels of thyroglobulin in patients who became hypothyroid by 12 months after treatment would support this view. Carbimazole pretreatment for eight weeks did not appear to protect against hypothyroidism, in our study.

The tumor necrosis factor beta * 1 allele is linked significantly to HLA-DR8 in Koreans with atrophic autoimmune thyroiditis who are positive for thyrotropin receptor blocking antibody

The localization and functional characteristics of tumor necrosis factor(TNF) beta gene raise the possibility that it may be involved in the susceptibility to autoimmune thyroid diseases. To investigate whether a TNF beta gene polymorphism is associated with autoimmune thyroiditis, we analyzed the TNF beta gene polymorphism with the restriction enzyme NcoI in 48 Korean patients with atrophic autoimmune thyroiditis [23 were found to be thyrotropin binding inhibitor immunoglobulin(TBII) positive, 25 TBII negative], 52 goitrous autoimmune thyroiditis, and 129 healthy controls. Two TNF beta alleles were identified from the restriction fragment length polymorphism studies of amplified genomic DNA. In atrophic autoimmune thyroiditis patients positive for TBII, 7 of 23 patients were homozygous for the TNF beta * 1 allele, 3 were homozygous for the TNF beta * 2 allele, and 13 were TNF beta * 1/2 heterozygous compared to controls(P = 0.20). Also, there were no associations between the TNF beta gene polymorphism and either TBII-negative atrophic autoimmune thyroiditis or goitrous autoimmune thyroiditis. Of the HLA-class II antigens, the frequency of HLA-DR8 was significantly greater among the 23 Korean patients with TBII-positive atrophic autoimmune thyroiditis compared to control subjects (Pc = 0.003). When the HLA-DR8 positive patients with TBII-positive atrophic autoimmune thyroiditis and controls were analyzed separately, the DR8 positive patients with TBII-positive atrophic autoimmune thyroiditis had more homozygotes for the TNF beta * 1 allele(6/12, 50.0%) and no homozygotes for the TNF beta * 2 allele, as compared to the DR8 negative patients with TBII-positive atrophic autoimmune thyroiditis and DR8 positive controls(P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Negative correlation between the conversion of thyrotropin receptor-bound blocking type thyrotropin receptor antibody to the stimulating type by anti-human IgG antibodies and the biological activity of blocking type thyrotropin receptor antibody

It has been reported that receptor-bound blocking type TSH receptor antibody (TRAb) can be converted to the stimulating type by anti-human IgG antibodies. To evaluate the relationship between the conversion of receptor-bound blocking type TRAb to the stimulating type and the biological activity of blocking type TRAb, we compared converting activities of blocking type TRAb from 10 patients with primary nongoitrous hypothyroidism with both the doses of blocking type TRAb which show 50% inhibition of 125I-bTSH binding to the TSH receptor and those which show 50% inhibition of TSH-stimulated cAMP production in cultured rat thyroid cells (FRTL-5). The additions of anti-human IgG antibody to FRTL-5 cell-bound blocking IgGs resulted in the increase in cAMP production in a dose-dependent manner and the converting activities (percent increase of cAMP production) also depended on the doses of blocking IgGs. The converting activities were significantly correlated with the doses of blocking IgGs which showed 50% inhibition of 125I-bTSH binding to the TSH receptor (r = 0.71, p = 0.011). And these converting activities were also significantly correlated with the doses of blocking IgGs which showed 50% inhibition of TSH-stimulated cAMP increase (r = 0.81, p = 0.002), and were negatively correlated with thyroid stimulation blocking antibody activities (r = 0.58, p = 0.02). We have demonstrated that all cell-bound blocking type TRAb were converted to the stimulating type by anti-human IgG antibody and the degree of conversion was negatively correlated with the biological activity of blocking type TRAb.(ABSTRACT TRUNCATED AT 250 WORDS)

Graves' disease: evolution and prognosis after eight months of treatment with methimazole

We studied 26 patients with Graves' disease, from a population with sufficient iodine supply, treated with high doses of methyl mercaptoimidazole (MMI) during eight moths. We evaluated: a) their evolution after treatment withdrawal; b) the correlation between evolution and TSH-receptor antibodies (TRAb), thyroid hormone levels, microsomal antibodies (MAb), T3/T4 index and clinical data; c) their prognosis. The patients were followed during 12-60 months, and blood samples were collected before treatment withdrawal. Out of 26 patients, 20 relapsed, with T3/T4 index and TRAb significantly higher than those under remission. The T3/T4 index correlated with TRAb. All the TRAb-positive patients, and only 57.1% of the negatives, relapsed. The relapses were significantly more frequent prior to the 6th month in the TRAb-positive patients than afterwards. The TRAb-negatives who relapsed during that period, showed TRAb and age means significantly higher than those under remission. The TRAb test, as a prognostic marker of evolution, showed a sensitivity of 60% and a specificity of 100%. No significant differences were found between evolution to relapse or to remission and the other parameters. It can be concluded that TRAb and T3/T4 index were different in the group that relapsed from that which remitted, and that a TRAb positive value, at the moment of treatment withdrawal, is a useful marker of relapse

Anticuerpos anti-receptor de TSH como indice de recidiva en la enfermedad de graves tratada con drogas antitiroideas / TSH receptor antibodies as a recurrence index of Graves' disease treated with antithyroid drugs

Estudiamos anticuerpos anti-receptor de TSH (TRAb), medido por un ensayo radioreceptor en suero total (TBir) en 54 pacientes con enfermedad de Graves sin tratamiento (grupo 1), 20 pacientes bajo tratamiento con metimazol (grupo 2) y 23 pacientes eutiroideos luego de completado un año de tratamiento con metimazol, una vez suspendida la terapia (grupo 3), para evaluar si TBir es útil como índice de recidiva en la enfermedad de Graves luego del tratamiento con drogas antitiroideas. En el grupo 1, TBir fue positivo en el 77,7% (45/54) de los casos. En el grupo 2 el 45% (9/20) tuvo valors positivos de TBir. Todos ellos recidivaron la enfermedad dentro del año posterior a finalizar la terapia. El 55% (11/20) tuvo TBir negativos, de ellos sólo el 18,1% (2/20) presentó recidiva en el mismo lapso de tiempo. Considerando globalmente a los pacientes del grupo 3, el 69,5% (16/23) fue TBir positivo. En el 75% (12/16) de los casos los valores anormales elevados de TBI fueron predictivos de la recidiva, mientras que el 71,43% (5/7) de pacientes con TBir negativos permanecia en remisión 12 meses después. De acuerdo al comportamiento de los valores de TBir antes y después del tratamiento, se establecieron distintos patrones de cambio: a) TBir persistentemente elevados: 52,17% (12/23). El 83,3% (10/112) presentó recidiva dentro de los seis meses de finalizada la terapia. b) TBir inicialmente elevado que se negativizó o se redujo en más del 50%: 26,09% (6/23). Todos los casos permanecían eutiroideos un año después de interrumpida la medicación. c) TBir persistentemente negativos: 13,04% (3/23): Dos presentaron recidiva. d) TBI negativo que cambió a positivo: 8,70% (2/23): Los dos presentaron recidiva. De acuerdo a los resultados obtenidos, consideramos útil como índice de recidiva valores de TBI anormalmente elevados durante o depués del tratamiento. En cambio, valores negativos de TBir después de la terapia, considerados aisladamente, no tienen valor pronóstico, debiendo evaluarse si existió un cambio en los valores iniciales