Nobuyuki Amino

TSH-suppressive doses of levothyroxine are required to achieve preoperative native serum triiodothyronine levels in patients who have undergone total thyroidectomy.

OBJECTIVEnThyroidal production of triiodothyronine (T(3)) is absent in patients who have undergone total thyroidectomy. Therefore, relative T(3) deficiency may occur during postoperative levothyroxine (L-T(4)) therapy. The objective of this study was to evaluate how the individual serum T(3) level changes between preoperative native thyroid function and postoperative L-T(4) therapy.nnnMETHODSnWe retrospectively studied 135 consecutive patients with papillary thyroid carcinoma, who underwent total thyroidectomy. Serum free T(4) (FT(4)), free T(3) (FT(3)), and TSH levels measured preoperatively were compared with those levels measured on postoperative L-T(4) therapy.nnnRESULTSnserum tsh levels during postoperative L-T(4) therapy were significantly decreased compared with native TSH levels (P<0.001). serum FT(4) levels were significantly increased (P<0.001). Serum FT(3) levels were significantly decreased (P=0.029). We divided the patients into four groups according to postoperative serum TSH levels: strongly suppressed (less than one-tenth of the lower limit); moderately suppressed (between one-tenth of the lower limit and the lower limit); normal limit; and more than upper limit. Patients with strongly suppressed TSH levels had serum FT(3) levels significantly higher than the native levels (P<0.001). Patients with moderately suppressed TSH levels had serum FT(3) levels equivalent to the native levels (P=0.51), and patients with normal TSH levels had significantly lower serum FT(3) levels (P<0.001).nnnCONCLUSIONSnSerum FT(3) levels during postoperative L-T(4) therapy were equivalent to the preoperative levels in patients with moderately suppressed TSH levels. Our study indicated that a moderately TSH-suppressive dose of L-T(4) is required to achieve the preoperative native serum T(3) levels in postoperative L-T(4) therapy.

Hashimoto's thyroiditis: history and future outlook.

Dr. Hakaru Hashimoto (Figure 1), born 5 May 1881, was the third son of a prominent family who had practiced medicine for generations in Iga Ueno, Mie Prefecture, Japan. He was one of the first graduates to receive a bachelor’s degree from the Fukuoka Medical College of Kyoto Imperial University in 1907. Hakaru Hashimoto received tutelage and training from Professor Miyake of the Department of Surgery of Fukuoka Medical College. Professor Miyake also instructed Dr. Hashimoto on the technique of assessing excised thyroid glands microscopically. In 1912, at the age of 30, Hakaru Hashimoto reported a distinct new disease in ‘Archiv fur Klinische Chirurgie”, a German journal of clinical surgery. His paper, which consisted of 30 pages and 5 illustrations and centered on histological changes in thyroid tissue, discussed the results of his examination of thyroid tissue samples taken from four women. Hakaru Hashimoto further explained in his report that the new pathological characteristics he had identified, namely infiltration of lymphoid and plasma cells, formation of lymphoid follicles with germinal centers, fibrosis, degenerated thyroid epithelial cells and leukocytes in the lumen, were histologically similar to those of Mikulicz’s disease. He expressed confidence that he had discovered a new disease, which he named “struma lymphomatosa”, emphasizing the lymphoid cell infiltration and formation of lymphoid follicles with germinal centers, neither of which had previously been reported.

Effect of the presence of remnant thyroid tissue on the serum thyroid hormone balance in thyroidectomized patients

OBJECTIVEnWe and others recently reported that in total thyroidectomy (TT), serum triiodothyronine (T3) levels during levothyroxine (L-T4) therapy were low compared to the preoperative levels, suggesting that the presence of the thyroid tissue affects the balances of serum thyroid hormone levels. However, the effects of remnant thyroid tissue on these balances in thyroidectomized patients have not been established.nnnMETHODSnWe retrospectively studied 253 euthyroid patients with papillary thyroid carcinoma who underwent a TT or hemithyroidectomy (HT). We divided the cases into the TT+supplemental L-T4 (+L-T4) group (n=103); the HT+L-T4 group (n=56); and the HT-alone group (n=94). We compared the postoperative serum levels of free T4 (FT4) and free T3 (FT3) and the FT3/FT4 ratio in individual patients with those of controls matched by serum TSH levels.nnnRESULTSnThe TT+L-T4 group had significantly higher FT4 (P<0.001), lower FT3 (P<0.01) and lower FT3/FT4 (P<0.001) levels compared to the controls. The HT+L-T4 group had FT4, FT3 and FT3/FT4 levels equivalent to those of the controls. The HT-alone group had significantly lower FT4 (P<0.01), equivalent FT3 (P=0.083), and significantly higher FT3/FT4 (P<0.001) ratios than the controls.nnnCONCLUSIONSnThe presence of the remnant thyroid tissue was associated with different thyroid hormone balances in thyroidectomized patients, suggesting that T3 production by remnant thyroid tissue has a substantial effect on the maintenance of postoperative serum T3 levels.

Thyroxine treatment may be useful for subclinical hypothyroidism in patients with female infertility

Infertile women sometimes associated with subclinical hypothyroidism (SCH). The guidelines of the American Endocrine Society, and American Association of Clinical Endocrinologists and American Thyroid Association recommend treatment with thyroxine (T4) for patients with SCH who want to have children. We examined 69 female infertile patients with SCH and the effects of levothyroxine (l-T4) therapy on pregnancy rates and pregnancy outcomes were observed. Fifty-eight (84.1%) patients successfully conceived during the T4 treatment period (Group A), although 17 patients (29.3%) had miscarriage afterward. The remaining 11 patients continued to be infertile (Group B). The median TSH value in Group A before the T4 treatment was 5.46 μIU/mL (range 3.1-13.3) and this significantly decreased to 1.25 μIU/mL (range 0.02-3.75) during the treatment (p<0.001). The estimated duration of infertility before the T4 treatment was 2.8±1.7 years and the duration until pregnancy after the treatment was significantly shorter at 0.9±0.9 years (p<0.001). Shortening of the infertile period after the T4 therapy was observed not only in patients who were treated with assisted reproductive technology (ART) but also in patients who conceived spontaneously in Group A. Administered T4 dose was 54.3±14.2 μg before pregnancy and 68.5±22.8 μg during pregnancy (p<0.001). Anti-thyroid autoantibodies were identified in 42.0% of all patients and no significant difference was observed in positivity between Group A and Group B. High successful pregnancy rate and shorter duration of infertility until pregnancy after T4 treatment strongly suggest that T4 enhanced fertility in infertile patients with SCH.

Kinetic analyses of changes in serum TSH receptor antibody values after total thyroidectomy in patients with Graves’ disease

We often recommend total thyroidectomy for patients with Graves disease who wish to have a child in the near future in order to prevent fetal or neonatal hyperthyroidism, especially if the patients serum thyrotropin receptor antibody (TRAb) values are high. The aim of this study was to analyze changes in serum TRAb values using a quantitative third-generation assay after total thyroidectomy and the half-lives of serum TRAb values to estimate the postoperative time needed to achieve the safe TRAb value for mothers. We retrospectively examined the records of 45 Graves disease patients who underwent a total thyroidectomy and had high serum TRAb values. We also evaluated factors that prolonged the postoperative reduction of serum TRAb values. The serum TRAb values decreased rapidly in most of the patients, especially within the early postoperative (3-month) period. The presence of Graves ophthalmopathy (GO) (p=0.001), smoking (p=0.004), and serum thyroglobulin values > 0.5 ng/mL at postoperative 12 months (p=0.039) were significantly associated with prolonged half-lives of the serum TRAb values. The median TRAb value half-life was 93.5 days in the patients without GO or smoking, 162.5 days in the patients with GO or smoking, and 357.4 days in the patients with both GO and smoking. Our findings indicate that using the half-life of patients serum TRAb values determined by this third-generation assay would be effective to evaluate the reduction of serum TRAb values after total thyroidectomy and to estimate the postoperative time needed to achieve the maternal safe value.

Graves' Disease Patients with Persistent Hyperthyroidism and Diffuse Lymphoplasmacytic Infiltration in the Thyroid Show No Histopathological Compatibility with IgG4-Related Disease.

Background IgG4-related disease is a novel disease entity characterized by diffuse lymphoplasmacytic infiltration rich in IgG4-positive plasma cells and fibrosis into multiple organs. There is still controversy over whether some thyroid diseases are actually IgG4-related disease. The objective of this study was to elucidate the clinicopathological features of Graves’ disease with diffuse lymphoplasmacytic infiltration in the thyroid. Patients and Methods Among 1,484 Graves’ disease patients who underwent thyroidectomy, we examined their histopathological findings including the degree of lymphoplasmacytic and fibrotic infiltration and levels of IgG4-positive plasma cells in the thyroid. Their clinical pictures were defined by laboratory and ultrasonographic evaluation. Results A total of 11 patients (0.74%) showed diffuse lymphoplasmacytic infiltration in the stroma of the thyroid gland. Meanwhile, other patients showed variable lymphoid infiltration ranging from absent to focally dense but no aggregation of plasma cells in the thyroid gland. Based on the diagnostic criteria of IgG4-related disease, 5 of the 11 subjects had specifically increased levels of IgG4-positive plasma cells in the thyroid. Fibrotic infiltration was present in only 1 patient developing hypothyroidism after anti-thyroid drug treatment for 4 years, but not in the other 10 patients with persistent hyperthyroidism. Obliterative phlebitis was not identified in any of the 11 subjects. Thyroid ultrasound examination showed 1 patient developing hypothyroidism who had diffuse hypoechogenicity, but the other hyperthyroid patients had a coarse echo texture. Conclusions In our study, Graves’ disease patients with persistent hyperthyroidism who had diffuse lymphoplasmacytic infiltration rich in IgG4-positive plasma cells in the thyroid showed no concomitant fibrosis or obliterative phlebitis.

A Novel Germline Mutation of KEAP1 (R483H) Associated with a Non-Toxic Multinodular Goiter.

Background A germline mutation of KEAP1 gene was reported as a novel genetic abnormality associated with familial multinodular goiter. That report was limited, and the pathogenic features were not well established. Patient findings We report a 47-year-old Japanese woman who presented with hyperthyroidism and a large multinodular goiter. The family history was notable for a paternal history of goiter. Graves’ disease was diagnosed based on positive TRAb, but scintiscan imaging showed that the patient’s radioiodine uptake was restricted in the non-nodular areas, indicating largely cold nodules. A total thyroidectomy was performed. The resected thyroid tissue weighed 209u2009g, and subsequent pathological findings were benign. The patient had a germline heterozygous KEAP1 mutation, c. 1448 Gu2009>u2009A, resulting in an amino acid substitution (p.R483H). A next-generation sequencing analysis covering all known genes associated with multinodular goiter showed no additional germline mutation. The nuclear accumulation of NRF2, a protein associated with KEAP1, was shown at much higher rates in the patient’s nodules compared with nodules obtained from four unrelated patients with multinodular goiters. Conclusion A novel germline mutation (R483H) of KEAP1 gene was associated with the development of a non-toxic multinodular goiter.

Comparison of thyroglobulin and thyroid peroxidase antibodies measured by five different kits in autoimmune thyroid diseases

It is generally believed that the detection of thyroid peroxidase antibodies (TPOAb) is superior to that of thyroglobulin antibodies (TgAb) for the diagnosis of Hashimotos thyroiditis. However, limited data are available on the comparison of TgAb and TPOAb prevalence as a diagnostic measurement for Hashimotos thyroiditis using sensitive immunoassays. We herein used five different current immunoassay kits (A-E) to compare the prevalence of TgAb and TPOAb in Hashimotos thyroiditis (n = 70), Graves disease (n = 70), painless thyroiditis (n = 50), and healthy control subjects (n = 100). In patients with Hashimotos thyroiditis, positive TgAb was significantly more frequent than positive TPOAb in kits A-D (mean ± SD of the four kits: 98.6 ± 1.7 vs 81.4 ± 2.0%). In patients with Graves disease, TgAb prevalence was almost equivalent to that of TPOAb in five kits. Patients with painless thyroiditis exhibited positive TgAb significantly more frequently than positive TPOAb in kits A-D (73.5 ± 4.1 vs 33.0 ± 3.4%). The prevalence of TgAb alone was significantly higher than that of TPOAb alone in both Hashimotos thyroiditis and painless thyroiditis in kits A-D. In kit E, TgAb and TPOAb prevalence did not differ significantly for any disease, and TgAb distribution was different from other kits. In conclusion, the prevalence of TgAb was higher than that of TPOAb in patients with Hashimotos thyroiditis and painless thyroiditis using commercially available kits. We suggest that TgAb immunoassay is the first choice of screening test for thyroid autoimmune abnormalities in Japan.