Ken Okamura

Proteomic analysis of human brain identifies α-enolase as a novel autoantigen in Hashimoto’s encephalopathy

Hashimotos encephalopathy (HE) is a rare autoimmune disease associated with Hashimotos thyroiditis (HT). To identify the HE‐related autoantigens, we developed a human brain proteome map using two‐dimensional electrophoresis and applied it to the immuno‐screening of brain proteins that react with autoantibodies in HE patients. After sequential MALDI‐TOF‐MASS analysis, immuno‐positive spots of 48 kDa (pI 7.3–7.8) detected from HE patient sera were identified as a novel autoimmuno‐antigen, α‐enolase, harboring several modifications. Specific high reactivities against human α‐enolase were significant in HE patients with excellent corticosteroid sensitivity, whereas the patients with fair or poor sensitivity to the corticosteroid treatment showed less reactivities than cut‐off level. Although a few HT patients showed faint reactions to α‐enolase, 95% of HT patients, patients with other neurological disorders, and healthy subjects tested were all negative. These results suggest that the detection of anti‐α‐enolase antibody is useful for defining HE‐related pathology, and this proteomic strategy is a powerful method for identifying autoantigens of various central nervous system diseases with unknown autoimmune etiologies.

A Sensitive Thyroid Stimulating Hormone Assay for Screening of Thyroid Functional Disorder in Elderly Japanese

The use of a screening test for thyroid functional disorder by sensitive thyroid stimulating hormone assay in the elderly was investigated. The basal thyroid stimulating hormone levels predicted the response of thyroid stimulating hormone to thyrotropin releasing hormone; it was suppressed in 99 (99.0%) of 100 hyperthyroid patients. Therefore, not only primary hypothyroidism but also hyperthyroidism can be excluded when the serum thyroid stimulating hormone levels are normal.

Thyroid function in Yusho patients exposed to polychlorinated biphenyls (PCB)

Thyroid function was investigated in 123 yusho patients who were exposed to toxic levels of polychlorinated biphenyls (PCBs) 16 years ago. In yusho patients, compared with the patients without evidence of yusho or normal controls, the serum triiodothyronine (T3) and thyroxine (T4) levels were significantly higher, while thyroid stimulating hormone (TSH) levels measured by sensitive assay were normal. There was no difference in serum levels of albumin, alkaline phosphatase, total cholesterol, and thyroxine binding globulin (TBG) between the two groups and the prevalence of positive antithyroid autoantibodies was almost the same, suggesting that hyperthyroxinemia in yusho patients was not due to increased TBG binding or abnormal autoimmune mechanism. Serum free T4 levels, however, were not elevated, although T4/TBG ratio was significantly higher. The thyroid hormone levels were higher than normal value in 4 of 123 yusho patients but only 1 case had clinical symptoms such as excessive perspiration. Despite higher serum PCBs in yusho patients, there was no correlation between PCB levels and levels of T3, T4, or TSH. The present results suggest hyperthyroxinemia without obvious clinical symptoms in yusho patients long after exposure to PCBs.

Identification of independent susceptible and protective HLA alleles in Japanese autoimmune thyroid disease and their epistasis.

BACKGROUND Autoimmune thyroid disease (AITD) includes Graves disease (GD) and Hashimoto thyroiditis (HT), which partially share immunological features. Determining the genetic basis that distinguishes GD and HT is a key to understanding the differences between these 2 related diseases. AIM The aims of this study were to identify HLA antigens that can explain the immunopathological difference between GD and HT and to elucidate epistatic interactions between protective and susceptible HLA alleles, which can delineate the distinct function of HLA in AITD etiology. DESIGN We genotyped 991 patients with AITD (547 patients with GD and 444 patients with HT) and 481 control subjects at the HLA-A, HLA-C, HLA-B, DRB1, DQB1, and DPB1 loci. A direct comparison of HLA antigen frequencies between GD and HT was performed. We further analyzed an epistatic interaction between the susceptible and protective HLA alleles in the development of GD and HT. RESULTS We identified 4 and 2 susceptible HLA molecules primarily associated with GD and HT, respectively, HLA-B*35:01, HLA-B*46:01, HLA-DRB1*14:03, and HLA-DPB1*05:01 for GD and HLA-A*02:07 and HLA-DRB4 for HT. In a direct comparison between GD and HT, we identified GD-specific susceptible class II molecules, HLA-DP5 (HLA-DPB1*05:01; Pc = 1.0 × 10(-9)) and HLA-DR14 (HLA-DRB*14:03; Pc = .0018). In contrast, HLA components on 3 common haplotypes in Japanese showed significant protective effects against the development of GD and HT (HLA-A*24:02-C*12:02-B*52:01-DRB1*15:02-DQB1*06:01-DPB1*09:01 and HLA-A*24:02-C*07:02-B*07:02-DRB1*01:01-DQB1*05:01-DPB1*04:02 haplotypes for GD and HLA-A*33:03-C*14:03-B*44:03-DRB1*13:02-DQB1*06:04-DPB1*04:01 haplotype for GD and HT). Interestingly, the representative protective HLA, HLA-DR13 (HLA-DRB1*13:02), was epistatic to susceptible HLA-DP5 in controlling the development of GD. CONCLUSION We show that HLA exerts a dual function, susceptibility and resistance, in controlling the development of GD and HT. We also show that the protective HLA allele is partially epistatic to the susceptible HLA allele in GD.

Reversible primary hypothyroidism in Japanese patients undergoing maintenance hemodialysis.

BACKGROUND/METHODS The presence or absence of hypothyroidism was assessed in 152 consecutive Japanese patients with end-stage renal disease on hemodialysis. Eight patients who had undergone treatment for thyroid disease before starting hemodialysis therapy, and 3 patients with amyloidosis due to rheumatoid arthritis were excluded. RESULTS Of the remaining 141 hemodialysis patients, 14 (9.9%) (9 males and 5 females, aged 69.1 A+/- 8.8 years with a mean duration of hemodialysis of 69 A+/- 51 months) were in a hypothyroid state, defined as a thyroid-stimulating hormone (TSH) level > 5 mU/l. Antithyroid peroxidase antibodies were positive in only 1 of the 14 patients, while antithyroglobulin antibodies were negative in all of these patients. After iodide restriction, the serum TSH level decreased in all the patients from a mean of 16.49 A+/- 22.80 to 4.44 A+/- 3.35 mU/l after 1 month, 4.25 A+/- 2.24 mU/l after 2 months and 3.97 A+/- 2.22 mU/l after 3 months. The 3 months of iodide restriction were also associated with decreases in systolic blood pressure (142 A+/- 19 to 125 A+/- 16 mmHg, p < 0.05), diastolic blood pressure (79 A+/- 13 to 72 A+/- 9 mmHg, p < 0.05) and thyroid gland volume estimated by ultrasonography (13.7 A+/- 6.3 to 11.6 A+/- 5.2 ml, p < 0.05). CONCLUSION A high prevalence of reversible primary hypothyroidism was found in end-stage renal disease patients on hemodialysis. Retention of excess iodide may be the mechanism responsible for reversible hypothyroidism rather than immunological perturbations. It is, therefore, recommended to attempt iodide restriction before starting l-thyroxine replacement therapy.

Reversible primary hypothyroidism with blocking or stimulating type TSH binding inhibitor immunoglobulin following recombinant interferon‐α therapy in patients with pre‐existing thyroid disorders

OBJECTIVE Treatment with recombinant interferon‐α (rIFN‐α) may induce autoimmunity. We have evaluated the effect of rIFN‐α on pre‐existing thyroid disease with special reference to changes in TSH receptor antibody.

Predominant T3 synthesis in the metastatic thyroid carcinoma in a patient with T3-toxicosis

A metastatic mixed papillary and follicular thyroid carcinoma synthesizing predominantly triiodothyronine (T3) producing thyrotoxicosis is described. There was a concentration of 131I in numerous masses on the lung as well as a mass in the neck. BMR was +38%. Serum T4, T3-RU and T3 were 6.6 microgram/100 ml, 35.1% and 9.0 ng/ml, respectively. Serum TSH was not detectable and was not increased by the injection of 500 microgram of synthetic TRH. Decompressive surgery, performed while the patient was receiving no thyroid medication, yielded tumor tissue for chemical analysis. The mass measured 4.5 cm X 4.0 cm X 3.0 cm. The normal thyroid tissue was found to be atrophic. Sedimentation pattern of the soluble protein revealed a small peak at 18 S without a 27 S peak, suggesting an accelerated hydrolysis of thyroglobulin (Tg). Both the Tg content of the tumor and the degree of iodination of the Tg were low, 0.53% (based on wet weight of tissue) and 0.07%, respectively. DIT-I, MIT-I, T4-I, and T3-I in hydrolysate of the tumor tissue were 17.8%, 29.1%, 7.1%, and 41.7%, respectively. Therefore, the high T3 in the serum in this case seems to arise mainly from the cancer tissue. Possible mechanisms for this predominant T3 production are discussed.

Immunological and chemical types of reversible hypothyroidism; clinical characteristics and long‐term prognosis

OBJECTIVE Spontaneous improvement occurs in about one‐half of patients with primary hypothyroidism who reside in an iodine‐sufficient area of Japan, but the pathogenetic factors related to reversible hypothyroidism are still not fully understood. We therefore investigated the clinical features and prognosis of patients with reversible hypothyroidism with or without iodine excess and antithyroid antibodies.

TSH DEPENDENT ELEVATION OF SERUM THYROGLOBULIN IN REVERSIBLE PRIMARY HYPOTHYROIDISM

Serum levels of thyroglobulin (Tg) were measured using immunoradiometric assay in 18 patients with primary hypothyroidism, whose serum levels of thyroid stimulating hormone (TSH) were higher than 40 mU/1 and anti‐Tg antibodies were negative. In 12 patients, serum Tg levels were extremely elevated above the upper limit of normal (30 ng/ml) and the levels were more than 800 ng/ml in 10 of them. In all of these 12 patients, thyroid function recovered spontaneously with only iodide restriction and the serum Tg levels declined concomitantly with the decrease in serum TSH concentrations, events suggesting the TSH dependency of this Tg elevation. In the other 6 patients without elevated Tg levels, thyroid function did not recover and replacement therapy with l‐thyroxine had to be given. Data from our study show that the TSH dependent Tg secretion is observed in reversible type primary hypothyroidism and that it may proceed vigorously even though thyroid hormone production is subnormal. Measurement of serum Tg may be valuable for predicting the prognosis of primary hypothyroidism.

Iodide-induced thyrotoxicosis in a thyroidectomized patient with metastatic thyroid carcinoma

An unusual case of iodide‐induced thyrotoxicosis is documented in this article. The patient was a 64‐year‐old euthyroid man with acromegaly. He also had multiple follicular and papillary thyroid carcinomas with a metastatic lesion in the lumbar vertebrae. After a total thyroidectomy, he became slightly hypothyroid, and the lumbar lesion began to incorporate 131I by scintigraphy. When an iodine‐containing contrast medium happened to be injected, a transient increase of serum thyroid hormone level was observed. After complete thyroid ablation with 83 mCi of 131I, the oral administration of 100 mg of potassium iodide for 7 days induced a prominent increase of serum thyroid hormone level. These findings indicated that the metastatic thyroid carcinoma could produce excess thyroid hormone insofar as a sufficient amount of iodide was given. Although this is the first report of such a case, iodide‐induced thyrotoxicosis may not be rare in patients with thyroid carcinomas because the Wolff‐Chaikoff effect is thought to be lost, and the organic iodinating activity and lysosomal protease activity are well‐preserved.