João H. Romaldini

High prevalence of thyroid autoantibodies in systemic sclerosis and rheumatoid arthritis but not in the antiphospholipid syndrome.

Abnormalities in thyroid function and thyroid autoantibodies have frequently been described in autoimmune diseases but seldom in antiphospholipid syndrome (APS) patients. We compared serum TSH, free T4 levels, thyroid antithyroglobulin (TgAb) and antithyroperoxidase (TPOAb) levels in 25 patients with systemic sclerosis (SS), 25 patients with rheumatoid arthritis (RA) and 13 patients with APS with those of a control group of 113 individuals. Evaluation included a thorough clinical examination and a serologic immune profile, including rheumatoid factor, antinuclear and anticardiolipin antibody measurements. Subclinical hypothyroidism was diagnosed in five patients and subclinical hyperthyroidism in four. TgAb and/or TPOAb was present in 21/63 of our patients: 52% of the SS cases (TPOAb=353±906 U/ml and TgAb=184±231 U/ml), 32% of the RA patients (TPOAb=41±65 U/ml and TgAb=196±559 U/ml), but in none of the APS patients (Fig. 1). Our data confirm a high prevalence of silent autoimmune thyroid diseases in association with SS and RA (p<0.02), but not with APS. Elevated antibody titers may reflect an epiphenomenon of the underlying autoimmune disorders and play an additive role in the development of the sick euthyroid syndrome in these patients, but our data suggest that APS presents a different pattern of response. Fig. 1 Prevalence of thyroid autoantibodies in patients with systemic sclerosis (SS), rheumatoid arthritis (RA) and antiphospholipid syndrome (APS) compared to control individuals Clin Rheumatol (2003) 22: 494 DOI 10.1007/s10067-003-0803-5

Disfunções mínimas da tiróide: hipotiroidismo subclínico e hipertiroidismo subclínico

Subclinical hypothyroidism (SHT) and subclinical hyperthyroidism (SCH) are defined as normal serum free T4 and T3 levels associated with elevated (SHT) or subnormal (SCH) serum TSH levels, respectively. Symptoms and signs of thyroid dysfunction are scarce. The prevalence is low. In SHT, total cholesterol and LDL-C are modestly elevated and levothyroxine may influence the lipids levels. There is decreased cardiac contractility and increased peripheral vascular resistance that improve with treatment. SCH is associated with atrial fibrillation, increased cardiac contractility and left ventricular mass, diastolic and systolic dysfunction that can be reversed with beta-adrenergic antagonists. Bone density is reduced in SCH. Depression, panic disorders and alterations in cognitive testing are frequent in SHT. Treatment of SHT is recommended for serum TSH levels greater than 8 mU/L and presence of thyroid antibodies. Endogenous SCH should be treated for serum TSH levels less than 0.1 mU/L, in the presence of symptoms and in elderly patents.

High serum TSH levels are associated with depression in the elderly

In order to investigate the association between elevated serum TSH levels and depression in the elderly, we conducted a population-based study of 451 over 60-year-old outpatients of a general University Hospital. Patients were divided into Group I (GI) (248 individuals) with high serum TSH levels, but otherwise no important condition or disease, and Group II (GII) (203 patients) with no previous diagnosis of thyroid or mood disease, referred to the hospital because of nonthyroidal severe diseases. All patients were clinically examined and classified according to DMS-IV for mood disturbance and had serum TSH, free T4 levels and antithyroid antibodies measured. High serum TSH levels (11.6+/-14.8 mU/l) were observed in 65/203 (32%) patients of GII. Among these patients, 42/65 (65%) had normal free T4 concentrations (1.23+/-0.98 ng/dl), no clinical manifestation of hypothyroidism and thus were considered to present subclinical hypothyroidism. Depression was observed in 24 cases from GI (9.7%) and 29 from GII (14.3%) and was frequent in the subclinical hypothyroid patients (49%). Our results suggest that mood disturbances are frequent in the elderly with elevated serum TSH levels, but they do not differ in the primary hypothyroid and the nonthyroidal sick patients.

Genetic polymorphisms associated with cigarette smoking and the risk of Graves’ disease

Objective  Cigarette smoking is a well‐recognized risk factor of Graves’ disease and, particularly, Graves’ ophthalmopathy. Hence, germline polymorphisms of detoxification genes and genes belonging to the major DNA repair–apoptosis pathways might have an important role in disease susceptibility. In addition, as some of these genes are regulated by thyroid hormones, they may affect the patients’ outcomes. We aimed to assess the influence of the GST, CYP and TP53 gene polymorphisms in the risk of Graves’ disease and its outcome.

Graves’ disease and Hashimoto’s thyroiditis: effects of high doses of antithyroid drugs on thyroid autoantibody levels

We studied the effects of high doses of methimazole (MMI) or propylthiouracil (PTU) on thyroid-stimulating antibody (TSAb), antithyroid microsomal (MCHA) and antithyroglobulin (TGHA) levels in Graves’ disease and Hashimoto’s thyroiditis. Thirty Graves’ hyperthyroid patients were treated for 14 ± 8 months (mean ± SD) with MMI, 60–80 mg daily or PTU, 900–1200 mg daily plus T3, 50–75 μg daily. Fifteen Hashimoto’s thyroiditis patients (4 of whom hypothyroid) received 100–200 μg of T4 daily for 4–8 weeks prior to MMI, 60–90 mg daily or PTU, 900 mg daily for 12–16 weeks. In Graves’ disease a decrease (p < 0.001) in TSAb activity (20/25 patients) was observed: before therapy, 0.424 ± 0.506 pmoles/mg wet wt and at the end of treatment, 0.189 ± 0.23 pmoles/mg wet wt. The MCHA titers also fell (18/26 patients) from 1:10,403 ±20,197 to 1:3,476 ± 5,252 (p < 0.01) and was associated with a decrease in free T4 values (1.23 ± 0.69 vs. 0.51 ± 0.36 ng/di; p<0.01). A fall of MCHA titers in T4-treated Hashimoto’s thyroiditis patients (1:10,416 ± 25,576) was found when compared with the value before T4 (1:25,920 ± 39,973; p < 0.001). However, the titers of MCHA (1:13,280 ± 25,992) did not change on MMI or PTU plus T4 treatment. The TGHA titers fell in a single patient. No alterations were observed in serum immunoglobulins. Serum concentrations of the complement factor C’3 remained higher (p < 0.01) than normal values in both Graves’ disease and Hashimoto’s thyroiditis. In conclusion, our data suggest that MMI and PTU have no influence on the immune system as a whole and the thyroid antibodies fall is due to a reduced thyroid antigen availability to the immune system and secondarily depends on the euthyroid status rather than on the antithyroid drug effect by itself.

A randomized controlled trial to evaluate the effectiveness of 2 regimens of fixed iodine (¹³¹I) doses for Graves disease treatment.

Aim: To investigate the effectiveness of 2 fixed iodine (131I) doses for the treatment for Graves hyperthyroidism and their impact on eye disease. Methods: We prospectively examined 76 patients who received a fixed dose of 370 MBq (group 1) and 52 patients who received 555 MBq 131I (group 2). Patients were followed up for 12 months and considered in remission when they were in a stable euthyroid or hypothyroid state in the absence of antithyroid drugs 12 months after 131I administration. Eight patients with active eye disease received a daily dose of 0.5 mg/kg prednisone per kilogram of body weight at the time of radioiodine therapy for 1 month. Results: The remission rate obtained was similar in groups 1 (73.7%) and 2 (80.8%; P = 0.35). Hypothyroidism was diagnosed in 56.5% of the 370-MBq group and 71.1% of the 555-MBq group patients (P = 0.13). There was no correlation among clinical features, thyroid uptake, antibody levels, serum hormones levels, and outcome. However, logistic regression analysis demonstrated that patients with large thyroid glands had 2.4 times less chance to go into remission (odds ratio; 95% confidence interval = 1.18–4.96). None of the patients developed eye disease during any fixed-dose treatment regimen or worsened their previously diagnosed ophthalmopathy. Conclusions: Fixed doses of 370 MBq and 555 MBq 131I provided similar remission rates; however, outcome was influenced by the thyroid size. We propose that 370 MBq 131I should be the routine treatment dose for all Graves disease patients, reserving a dose of 555 MBq 131I to palpable large goiters, without any additional concern to eye disease.

Spontaneous hypothyroidism in the follow up of Graves hyperthyroid patients treated with antithyroid drugs.

Aim: Spontaneous hypothyroidism may follow the natural course of Graves disease (GD) after treatment with antithyroid drugs (ATD). Methods: We studied retrospectively 139 remitted Graves hyperthyroid patients treated with ATD, with a follow-up period of 17.5 years (range 6 to 25 years). Elevated serum concentration of thyroid-stimulating hormone and low serum thyroxine concentrations confirmed the diagnosis. Results: Thirteen patients (median age, 41 years; 26 to 48 years) developed spontaneous hypothyroidism, 4 to 144 months (median, 48 months) following withdrawal of ATD. The prevalence of hypothyroidism was 9.3% and the incidence was 2.3% per year (13/563.6 patients/year of observation). There was no association with types of drugs used or the regimens. Spontaneous hypothyroid patients showed elevated titers (P = 0.02) of serum antithyroid peroxidase antibody (TPOAb) at the end of treatment with ATD, compared with the titers found at the beginning. These patients also had higher titers of TPOAb (P = 0.01) in relation to euthyroid patients. In contrast, the changes in serum antithyroglobulin antibody titers were not significant. Conclusions: Because of the shift from euthyroidism to spontaneous hypothyroidism, GD patients demanded a strict follow up after ATD therapy. It seems that there is an effect of TPOAb on thyroid destruction.

Is diffuse and peritumoral lymphocyte infiltration in papillary thyroid cancer a marker of good prognosis

Background: Papillary thyroid carcinoma (PTC) is the most frequently diagnosed endocrine neoplasia, representing 70 to 80% of all diagnosed thyroid cancers. Furthermore, Hashimoto’s thyroiditis is a frequent inflammatory thyroid disease and the main cause of hypothyroidism. The relationship between Hashimoto’s thyroiditis and PTC remains controversial. Methods: Surgery for PTC was performed at our institution on 157 consecutive patients. They were classified by the degree of lymphocyte infiltration (LI). LI was classified as diffuse LI or peritumoral LI (only in or around the tumor), or absent. In addition, age, gender, tumor size, histopathological findings, lymph-node metastasis, extra-thyroidal extension, multifocal tumor, coexistence of LI and clinical outcomes were analyzed. Results: Out of the 141 patients included in the study, 83 (59%) had diffuse LI and 22 (16%) had peritumoral LI. In 36 patients (25%) LI was absent. A comparison of patients in the 3 groups revealed no significant difference in their genders, ages, smoking status, thyroid function, or nodule size at the time of surgery. The characteristics of PTC showed no differences in lymph-node metastasis, tumor invasion into contiguous neck structures, angioinvasion, or PTC subtypes. Tumor-node-metastasis (TNM) classification and classes did not differ among the 3 groups. During the follow-up, 64 out of 141 patients with PTC (55%) had recurrences from 6 to 130 months after the initial treatment. After a mean follow-up period of 8 yr we observed a significantly (p=0.01) high recurrence (66.6%) in the LI absent group with 24 of 36 patients when compared to patients from the diffuse LI group (32 out of 83 patients; 38.5%) and peritumoral LI group (8 out of 22 patients; 25%). Conclusions: Although the role of the inflammatory-immune cells is complex and little understood, we found a more favorable course of PTC in the presence of LI (diffuse or peritumoral); this supports the hypothesis that LI represents a form of immune reaction to control tumor growth and proliferation.

The evolution of Graves’ ophthalmopathy during treatment with antithyroid drug alone and combined with triiodothyronine

We analyzed the evolution of the ophthalmopathy associated with Graves’ hyperthyroidism in 45 patients treated with two different antithyroid drug regimens. Group A patients (n = 31) received either methimazole (40–100 mg daily) or propylthiouracil (400–900 mg daily) combined with T3 daily throughout treatment. Group B patients (n = 14) were treated with conventional regimen with lower doses of either methimazole (5–25 mg daily) or propylthiouracil (50–300 mg daily) and no T3 addition. Eye signs and proptosis measurement were evaluated just before the beginning of the treatment and compared with the results after antithyroid drug withdrawal. Improvement of the eye signs considered on grounds of the NOSPECS classification was greater in group A than group B (p < 0.01 ). Also, the decrease in proptosis measurement was greater (p < 0.01) in patients treated with combined regimen (21.5 ± 2.4 mm to 20.4 ± 2.3 mm) than in patients receiving conventional therapy (20.4 ± 1.6 mm to 20.0 ± 1.7 mm). Serum thyroglobulin concentrations did not correlate with either the severity or the evolution of the ophthalmopathy. Negative serum antithyroglobulin antibody (TgAb) was associated with the improvement of the ophthalmopathy that was noted in 24 out of 27 patients (Chi-Square = 5.84; p < 0.001). Thus, serum TgAb levels might have some connection with progression of eye signs but serum Tg concentration does not. Our study suggests that in most patients the transition from hyperthyroidism to euthyroidism induced by antithyroid drug therapy is associated with the improvement of the Graves’ ophthalmopathy. However, no marked difference can be drawn between the two treatment regimens.

Avaliação do peso corporal em pacientes com doença de Graves durante o tratamento com metimazol

OBJECTIVE To evaluate weight change during hyperthyroidism treatment, and to correlate it with IL-6 and TNF-alpha concentrations. SUBJECTS AND METHODS Forty two patients were included. Body weight (BW), body mass index (BMI), clinical and laboratory characteristics were recorded. IL-6 and TNF-alpha were determined before treatment with methimazole (MMI) and in euthyroidism. RESULTS BW was 59.62 ± 11.5 kg in hyperthyroidism, and 69.91 ± 14.4 kg in euthyroidism (p < 0.001). BMI increased from 23.1 ± 3.8 kg/m(2) to 27 kg/m(2) ± 4.7 during treatment (p < 0.0001). Before treatment, 66.6% subjects had BMI < 25 kg/m(2) and 33.3%, BMI > 25 kg/m(2). In euthyroidism, 38% of patients had BMI < 25 kg/m(2) and 62%, BMI > 25 kg/m(2) (p = 0.01). In euthyroidism, we found a significant reduction in IL-6 and TNF-alpha concentrations, but no correlation between IL-6 and TNF-alpha, and BW or BMI. CONCLUSION An important increase in BW and BMI was observed during hyperthyroidism treatment, and IL-6 and TNF-alpha alterations were only related with return to euthyroidism.