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Arango-Filho et al., from
the University Hospital, São Paulo Medical School, Brazil,
reported on the presence of thyroid carcinoma in seven patients
with clinical Graves’ disease. All patients had a thyroid
nodule with variable size (2–65 mm). The reported prevalence
of differentiated cancer in Graves’disease is 0.6 to 5.0%.
In the present paper the surgical team performed a total
thyroidectomy and the pathological diagnosis was papillary cancer
in all seven patients. One patient developed mediastinal
metastasis in lymph nodes, confirmed by scintiscan. All patients
were submitted to a therapeutic dose of radioactive iodine. The
follow-up of 36 months indicated that no further recurrence of
the cancer has occurred.
Serum cytokines may be increased in patients with Graves’ hyperthyroidism as reported by Pegoraro et al., Hospital IAMSPE, São Paulo, Brazil. Raised serum levels of TNF-a, IL-6, soluble IL-2 receptor (sIL-2R), IL-8 and a decreased concentration of IL-1b has been demonstrated in hyperthyroid patients but it has been difficult to discriminate between the contribution of elevated thyroid hormones and of the autoimmune mechanisms present in Graves’ disease to these changes. The authors undertook a longitudinal study of 31 patients with Graves’ hyperthyroidism studied before treatment and after 16–20 weeks following methimazole (MMI) treatment with or without L-T3 addition. Controls included 23 normal subjects. Circulating cytokines were measured by ELISA and expressed in pg/ml. When compared with controls (median and range IL-lb 19.7, 4.7–71.2; sIL-2R 330, 146–712; lL-6 4.3, 1.5–14.4; IL-8 6.6, 3–10 and TNF-a 15, 4.4–21) untreated patients had elevated serum lL-1b (40, 11.5–320; p<0.0001), slL-2R (1141, 355–3774; p<0.0001), lL-6 (10.8, 3–122; p<0.001) but normal serum levels of IL-8 (6.7, 2.6–84) and TNF-a (10.3, 2.3–140). After restoring euthyroidism there was a decline of sIL-2R (352, 153–1006; p<0.0001), IL-6 (4.1–40; p<0.001) and TNF-a (4.4, 3–45; p<0.01) but no significant alteration occurred in lL-1b (38, 5–100) and IL-8 (10, 2–36) levels. The sIL-2R and IL-6 levels fell to near control levels. Both sIL-2R and IL-6 levels correlated with serum T3 (0.70; p<0.001 and 0.27; p<0.03, respectively) and only slL-2R correlated with serum free T4 (0.82; p<0.0001). The authors concluded that soluble IL-2 receptor and IL-6 appears to be related to thyroid hormone levels and TNF-a may be influenced by the MMI treatment of Graves’disease. Moreover, the serum concentration of the cytokines may be used as predictor of recurrence of the disease. Further studies will be necessary to test this hypothesis. Silva et al., from the Cardiology Institute of the State of Santa Catarina, Brazil, reported on endocarditis occurring during methimazole induced agranulocytosis in a patient who was treated with recombinant granylocyte-monocyte colony stimulating factor (rHu GM-CSF). Agranulocytosis caused by hypoplasia of the bone marrow is a rare and severe complication of antithyroid drugs. The use of rHu GM-CSF has been proposed with controversial results and very few cases have been reported. The authors present a rare case of an adolescent patient with bacterial endocarditis of the pulmonary valve caused by Klebsiella sp. and agranulocytosis caused by severe hypoplasia of the bone marrow after initial treatment of thirty days with methimazole for hyperthyroid Grave's disease. Preceding the use of methimazole, the patient presented with an oropharyngeal infection suggesting a tendency of suppression of the immune system. Proponents of rHu GM-CSF therapy state that an adequate response on the numbers of granulocytes occurs within five days, on average. In the present case recovery of peripheral granulocytes occurred after twelve days, without addition of corticosteroids. A bone marrow biopsy after four days of treatment may be indicative of the initial response to rHu GM-CSF. It has also been reported that determination of HLA antigen would indicate patients who will be susceptible to thionamide-induced agranulocytosis (comment: The susceptibility of agranulocytosis may be HLA-linked, as suggested by TAMAI et al., Ann Int Med 124:490, 1996). The effectiveness of radioiodine in the treatment of Graves’disease may be altered by the previous use of antithyroid drugs as reported by Santos et al. from UNICAMP, Campinas, Brazil. Antithyroid drugs (ATD) are largely used as initial treatment for Graves’ disease, mainly in Japan, Europe and also in South America. When remission is not attained with these drugs, patients are referred to I131 therapy. However, premedication with thionamides has been shown to reduce therapeutic effectiveness of radioiodine. DS Cooper (Endocr Metab Clin North America 27:229, 1998) described a lower cure rate in patients treated with propylthyouracil (PTU) (24%) as compared with the subjects who did not receive any drug (66%). Patients who received methimazole (MMI) prior to radioiodine had a similar cure rate (61%) as patients without previous medication. In order to assess the patients' outcome, the authors examined 62 Graves’ disease patients 3, 9 and 12 months after a 10 mCi standard dose of I131. Patients were randomly assigned to a group PTU-, MMI- or no thionamides pre-treatment. Cure of hyperthyroidism was defined by clinical and laboratory evidence of euthyroidism or hypothyroidism in the absence of ATD, 6 months after I131. The 3 groups were statistically similar concerning mean age, thyroid volume and 24h-radioiodine uptake. The results show that the MMI group (28 cases) and the group that did not receive any ATD (16 cases) present a similar cure rate (72% and 75% respectively). Conversely the PTU group (18 patients) showed a cure rate of only 33% (p<0.05). The authors suggest that the use of PTU as pre-treatment reduces the cure rate of Graves’disease by radioiodine therapy. Velez et al., Santiago de Chile, retrospectively examined the records of 325 patients of whom about half were pre-treated with PTU and the other half received no drug therapy before radioiodine administration. While patients with PTU pre-treatment attained in 50% cure (eu- or hypothyroidism), 75% of patients receiving RAI, without PTU pre-treatment were considered cured of Graves’disease. They similarly concluded that pre-treatment with PTU reduces the efficacy of RAI. Iorcanksy et al., from the Garrahan Pediatrics Hospital, Buenos Aires, Argentina, have indicated that low doses of methimazole (LD-MMI) inhibit hormonal synthesis and were able to modulate the immune response in juvenile hyperthyroidism (JH). The target of the antithyroid drugs (MMI, PTU) is inactivation of thyroid peroxidase with a progressive blocking of hormone synthesis. However, these drugs seem to have also the capacity of interfering with the immunologic mechanisms involved in the pathogenesis of hyperthyroidism. It is well known that MMI treatment decreases antithyroid antibodies (TAb) in most of the patients. In order to evaluate the LD-MMI inhibitory and ímmuno-modulatory actions in juvenile hyperthyroidism (JH), serum TSH levels and TAb antimicrosomal (Mi-Ab) and antíthyroglobulin (Tg-Ab), were measured immediately before and 1–3 months after withdrawal of LD-MMI in patients who went into remission. All received MMI (1mg/kg/d) as initial treatment and MMI was reduced progressively to LD-MMI (1–5mg/d). LD-MMI was discontinued when TSH levels stayed in a value of ?2µU/ml for a minimum of 3 months. Of the whole group of 63 JH patients, 21 (33%) (11.7±3.9y), went into remission between 14 and 83 months of treatment. After remission, these patients were followed for 16 to 60 months. Three patients initially considered to be in remission relapsed between 5 to 12 months after LD-MMI was discontinued. The authors analyzed thyroid function tests, TSH and auto-antibodies immediately before (pre) and 1–3 months (post) after withdrawal of MMI and the results were as follows: Serum TSH (µU/ml): in 17/21 diminished significantly (mean pre 3.82 ±1.78; post 1.49 ± 1.13; paired "t" test: p<0.001); 4/21 showed mild increase. Mi-Ab: titres increased in 17/21 patients (median pre 1/25600; post 1/409600; Tg-ab median pre: 1/1600; post 1/25,600: p<0.001). None of the 3 patients who relapsed showed increased titres of Mi-Ab. Tg-Ab: titres increased, but not significantly, in 5/21 patients. None of the 3 patients who relapsed, showed increased titres of Mi-Ab. Tg-Ab: titres increased, but not significantly, in 5/21 patients. The 3 patients who relapsed maintained equal levels of Tg-Ab. The authors concluded that: (1) Low doses of MMI (LD-MMI) maintain inhibition of hormonal synthesis documented by the fact that discontinuing the LD-MMI serum TSH levels decreased significantly; (2) The titres of Mi-Ab increased significantly after withdrawal of MMI (an immunomodulatory effect of MMI); (3) the immunomodulatory action of MMI could be related to the reduction or structural modification of the TPO antigen. Two different groups have studied the effect of different forms of treatment of Graves’disease. Pineda et al. from Chile, followed 226 patients for a period of five years after the first examination. Sixty-eight patients (59 F) from this group were still euthyroid after 112 months of observation. In the table the type of treatment and the results of the therapeutic modality after 5 years of follow-up, are indicated (table 3). Patients who were submitted to surgery had larger goiters. Hypothyroidism was more frequent in patients who received radioiodine. Patients who were initially treated with PTU but were subsequently submitted to surgery or RAI had larger goiters than PTU-only patients. Tokars et al. from Curitiba, PR, Brazil, evaluated the fate of patients clinically treated with AT drugs for Graves’disease and followed up for 10 years (1988–1998). They reported on 623 patients who received ATD alone or in combination with 100 µg of L-Thyroxine. The first conclusion of this paper was, surprisingly, that the combination of L-T4 increased significantly the number of patients who went into permanent remission. Other factors favoring remission were: small goiters (<50g) and age over 40 years. A reduced chance of remission (e.g. large goiters) should be a strong argument for radioiodine or surgery. (comment: The notion that thyroid hormone given during or after a course of anthithyroid drug therapy might enhance remission rates is not new. This idea was originally tested and subsequently confirmed by Hashishume et al. (N Engl J Med 325:447, 1991). Other similarly designed prospective randomized studies were unable to confirm these results. (see Cooper DS review for references Endocr Metab N Am 27[1]:225, 1998}. The majority of evidence indicates that it is not helpful to use combined antithyroid drug-thyroxine therapy to enhance the chances of remission). Table 3
PTU: propylthiouracil S: Surgery RAI: radioiodine |
