Graves' disease and mental disorders.

Mental disorders merge highly with thyroid diseases. Because of its regulatory effects on serotonin and noradrenalin, T3 has been linked closely to depression and anxiety. It has known that in many cases, the mental symptoms persist even after normalization of thyroid function by treatment. Psychosocial factors including stress have been associated with mental symptoms even after thyroid function normalization in Graves' disease and a combination of mental disorders have been related to the exacerbation of hyperthyroidism. These findings suggest that psychosomatic approaches based on the bio-psycho-social medical model are important for the treatment of mental disorders associated with Graves' disease.

Effect of levo-thyroxine replacement on non-high-density lipoprotein cholesterol in hypothyroid patients.

CONTEXT: Recently, non-high-density lipoprotein cholesterol (non-HDL-C), a measure of total cholesterol minus HDL-C, has emerged as a predictor of cardiovascular disease. OBJECTIVE: We evaluated the effect of L-T4 replacement on non-HDL-C levels in patients with primary hypothyroidism. METHODS: Thirteen patients with overt hypothyroidism and 26 patients with subclinical hypothyroidism participated in the study. The lipid profiles, including non-HDL-C, were measured in patients with hypothyroidism before and 3 months after L-T4 replacement was started. RESULTS: After L-T4 replacement, the serum concentrations of all lipoproteins, exclusive of lipoprotein (a) [Lp(a)], were significantly decreased in patients with overt hypothyroidism. In patients with subclinical hypothyroidism, the serum concentrations of total cholesterol, non-HDL-C, remnant-like particle cholesterol, and apolipoprotein B (Apo B) were significantly decreased, whereas no significant changes in the serum concentrations of low-density lipoprotein cholesterol, HDL-C, triglycerides, apolipoprotein A-I, and Lp(a) were observed. In all 39 patients, the reduction in the non-HDL-C levels correlated with the reduction in the low-density lipoprotein cholesterol, remnant-like particle cholesterol, and Apo B levels. However, the reduction in the non-HDL-C levels did not correlate with the reduction in the HDL-C, Lp(a), and apolipoprotein A-I levels. CONCLUSIONS: This study is the first to show that L-T4 replacement may reduce serum concentrations of non-HDL-C in patients with hypothyroidism. The study also suggests that such altered serum concentrations of non-HDL-C in hypothyroidism may be related to the disturbed metabolism of low-density lipoprotein, remnant lipoprotein, and Apo B.

DUOX2 Gene Mutation Manifesting as Resistance to Thyrotropin Phenotype.

Resistance to thyrotropin (TSH) (RTSH; defined by elevated TSH and a normal or hypoplastic thyroid gland) can be caused by mutations in genes encoding the TSH receptor and PAX8, and it has been linked to a locus on chromosome 15. In two nonconsanguineous families with nongoitrous euthyroid hyperthyrotropinemia, typical of the RTSH phenotype, exome analysis identified five rare DUOX2 gene variants (p.A649E, p.P1391A, p.R885L, p.G488R, and p.SF965-6SfsX29) found to be pathogenic. This form of nongoitrous dyshormonogenesis masquerades both clinically and biochemically as RTSH. Accordingly, mutations in DUOX2 should be added to those of SLC26A4 as causes of RTSH.

Haplotype analysis reveals founder effects of thyroglobulin gene mutations C1058R and C1977S in Japan.

CONTEXT: Thyroglobulin (Tg) mutations were previously believed to be rare, resulting in congenital goitrous hypothyroidism. However, an increasing number of patients with Tg mutations, who are euthyroid to mildly hypothyroid, have been identified in Japan. OBJECTIVES: The purpose of this study was to investigate whether the three frequently found Tg mutations, namely C1058R, C1245R, and C1977S, were caused by a founder effect. RESULTS: We found 26 different mutations within the Tg gene in 52 patients from 41 families. Thirty-five patients were homozygous for the mutations, whereas the others were compound heterozygous. The occurrence of Tg mutation within the general Japanese population is one in 67,000. Patients with the C1245R mutation were found throughout Japan, whereas those with the C1058R mutation were confined to a small village on a southern island, and those with the C1977S mutation were restricted to a city. The eight patients with the C1058R mutation and the seven patients with the C1977S mutation all showed the same combinations of 18 single-nucleotide polymorphisms in the coding region of the Tg gene, which would appear in one in 810 million and one in 37 billion, respectively, control subjects. CONCLUSIONS: The frequently found mutations, C1058R and C1977S, were caused by founder effects. This result suggests that Tg mutations may provide a genetic basis for the cause of familial euthyroid goiter.

High diagnostic value of a radioiodine uptake test with and without iodine restriction in Graves' disease and silent thyroiditis.

The necessity of iodine restriction before radioiodine uptake (RAIU) testing for differentiation of thyrotoxicosis is controversial. The present study was undertaken to investigate the effects of iodine restriction on the RAIU value, and the necessity of iodine restriction in differentiating between Graves' disease (GD) and silent thyroiditis (ST). We investigated 415 patients, 277 of whom were patients with GD who had undergone iodine restriction before RAIU [GD(+)], 66 were patients with GD who did not undergo iodine restriction [GD(-)], 61 were patients with ST who had undergone iodine restriction [ST(+)], and the remaining 11 were patients with ST who did not undergo iodine restriction [ST(-)]. The RAIU value of the GD(+) group, 47.6% +/-14.4% (mean +/-standard deviation [SD]), was significantly higher than that of the GD(-) group, 42.4% +/- 17.6% (p = 0.03). However, the areas under the curves from the receiver operator characteristics analyses for the comparison between groups GD(+)/ST(+), GD(+)/ST(-), GD(-)/ST(+) and GD(-)/ST(-) were 0.99967, 0.99967, 0.98436, and 0.98485, and very high, respectively. High diagnostic value of the RAIU test was confirmed, but not affected by the presence of iodine restriction in the differentiation between GD and ST, therefore, iodine restriction before the RAIU test was unnecessary.

The thyroid function of Graves' disease patients is aggravated by depressive personality during antithyroid drug treatment.

BACKGROUND: We previously reported that depressive personality (the scores of hypochondriasis, depression and psychasthenia determined by the Minnesota Multiphasic Personality Inventory (MMPI)) and daily hassles of Graves' disease (GD) patients treated long trem with antithyroid drug (ATD) were significantly higher in a relapsed group than in a remitted group, even in the euthyroid state. The present study aims to examine the relationship among depressive personality, emotional stresses, thyroid function and the prognosis of hyperthyroidism in newly diagnosed GD patients. METHODS: Sixty-four untreated GD patients responded to the MMPI for personality traits, the Natsume's Stress Inventory for major life events, and the Hayashi's Daily Life Stress Inventory for daily life stresses before and during ATD treatment. RESULTS: In the untreated thyrotoxic state, depressive personality (T-scores of hypochondriasis, depression or psychasthenia greater than 60 points in MMPI) were found for 44 patients (69%). For 15 (23%) of these patients, the scores decreased to the normal range after treatment. However, depressive personality persisted after treatment in the remaining 29 patients (46%). Normal scores before treatment were found for 20 patients (31%), and the scores were persistently normal for 15 patients (23%). The remaining 5 patients (8%) had higher depressive personality after treatment. Such depressive personality was not associated with the severity of hyperthyroidism. Serum TSH receptor antibody activity at three years after treatment was significantly (p = 0.0351) greater in the depression group than in the non- depression group. The remission rate at four years after treatment was significantly (p = 0.0305) lower in the depression group than in the non- depression group (22% vs 52%). CONCLUSION: The data indicate that in GD patients treated with ATD, depressive personality during treatment reflects the effect of emotional stress more than that of thyrotoxicosis and that it aggravates hyperthyroidism. Psychosomatic therapeutic approaches including antipsychiatric drugs and/or psychotherapy appears to be useful for improving the prognosis of hyperthyroidism.

Type 1 and type 2 iodothyronine deiodinases in the thyroid gland of patients with 3,5,3'-triiodothyronine-predominant Graves' disease.

OBJECTIVE: 3,5,3'-triiodothyronine-predominant Graves' disease (T(3)-P-GD) is characterized by a persistently high serum T(3) level and normal or even lower serum thyroxine (T(4)) level during antithyroid drug therapy. The source of this high serum T(3) level has not been clarified. Our objective was to evaluate the contribution of type 1 and type 2 iodothyronine deiodinase (D1 (or DIO1) and D2 (or DIO2) respectively) in the thyroid gland to the high serum T(3) level in T(3)-P-GD. METHODS: We measured the activity and mRNA level of both D1 and D2 in the thyroid tissues of patients with T(3)-P-GD (n=13) and common-type GD (CT-GD) (n=18) who had been treated with methimazole up until thyroidectomy. RESULTS: Thyroidal D1 activity in patients with T(3)-P-GD (492.7±201.3 pmol/mg prot per h) was significantly higher (P<0.05) than that in patients with CT-GD (320.7±151.9 pmol/mg prot per h). On the other hand, thyroidal D2 activity in patients with T(3)-P-GD (823.9±596.4 fmol/mg prot per h) was markedly higher (P<0.005) than that in patients with CT-GD (194.8±131.6 fmol/mg prot per h). There was a significant correlation between the thyroidal D1 activity in patients with T(3)-P-GD and CT-GD and the serum FT(3)-to-FT(4) ratio (r=0.370, P<0.05). Moreover, there was a strong correlation between the thyroidal D2 activity in those patients and the serum FT(3)-to-FT(4) ratio (r=0.676, P<0.001). CONCLUSIONS: Our results suggest that the increment of thyroidal deiodinase activity, namely D1 and especially D2 activities, may be responsible for the higher serum FT(3)-to-FT(4) ratio in T(3)-P-GD.

The relationship of psychological factors to the prognosis of hyperthyroidism in antithyroid drug-treated patients with Graves' disease.

OBJECTIVE: The relationship between emotional stress and the onset of hyperthyroidism has been well investigated, but the relationship between psychological factors and prognosis of antithyroid drug-treated hyperthyroidism is not well known. This study has examined not only emotional stresses but also patients' personality traits using specific tests. DESIGN: A prospective cohort study. SUBJECTS: Sixty-nine patients with hyperthyroid Graves' disease in the euthyroid state after 2-5 years of antithyroid drug therapy and 32 healthy subjects as the control group. MEASUREMENTS: Patients responded to three types of questionnaires, including the Minnesota Multiphasic Personality Inventory for personality traits, the Natsume's Stress Inventory for major life events, and the Hayashi's Daily Life Stress Inventory for daily life stresses. RESULTS: In the Graves' disease patients, stress scores of life events correlated significantly with serum TSH receptor antibody activity (r = 0.424, P < 0.001) and thyroid volume (r = 0.480, P < 0.001). When the patients were divided according to prognosis (41 with relapse and 28 with remission), four personality traits including hypochondriasis, depression, paranoia and psychasthenia (mental fatigue) were significantly (P = 0.0146, 0.0052, 0.0125, and 0.0186, respectively) more common in the relapsed Graves' disease group than those of the remitted group. Six personality traits of conversion hysteria, psychopathic deviation, masculinity and feminity, schizophrenia, hypomania, and social introversion were not significantly different between the two groups. The scores of daily hassles (problems of daily life) were also significantly (P = 0.0124) greater in the relapsed Graves' disease group than in the remitted group. The scale scores of depression and psychasthenia showed a positive correlation with scores of daily hassles (r = 0.535, P < 0.0001; r = 0.580, P < 0.0001, respectively), while an inverse correlation with scores of daily uplifts (r = -0.373, P = 0.0332; r = -0.322, P = -0.0120, respectively). CONCLUSIONS: The results suggest that major life events, personality traits of hypochondriasis and depression, paranoia, mental fatigue, and daily problems aggravate the prognosis of antithyroid drug-treated hyperthyroidism. Escape from life events is virtually impossible; thus coping strategies suggested by the physician may be useful in improving prognosis in Graves' disease.

Serum concentrations of granulocyte colony-stimulating factor (G-CSF) in antithyroid drug-induced agranulocytosis.

Granulocyte colony-stimulating factor (G-CSF) levels in serum were determined by a highly-sensitive chemiluminescent enzyme immunoassay (limit of detection, 0.5 pg/ml) in 54 patients with Graves' disease including 6 patients complicated with methimazole-induced agranulocytosis. Serum G-CSF levels in patients with Graves' disease were not different from normal subjects and did not correlate with serum FT4 level or circulating neutrophil counts. Before the onset of agranulocytosis, there was no difference in serum G-CSF level between the patients complicated with agranulocytosis and the uncomplicated patients. When circulating neutrophil counts decreased to less than 0.5 x 10(9)/L, serum G-CSF level elevated with the mean of 106.8 +/- 82.2 (SD) pg/ml, but the level did not correlate with the duration of agranulocytosis. Interestingly, maximum serum G-CSF level during the treatment with recombinant human G-CSF (100 microg/day) was related to bone marrow finding at the onset of agranulocytosis and correlated with the duration of agranulocytosis (r = 0.824, p < 0.05). In conclusion, measuring serum G-CSF levels with a highly-sensitive chemiluminescent enzyme immunoassay revealed that 1) thyrotoxicosis does not affect serum G-CSF level, 2) serum G-CSF level during antithyroid drug treatment does not play an important role in development of agranulocytosis, 3) the maximum serum G-CSF level in the course of agranulocytosis is related to the responsiveness of bone marrow to G-CSF and the recovery time from agranulocytosis.

Serum concentrations of remnant-like particles in hypothyroid patients before and after thyroxine replacement.

OBJECTIVES: Remnant-like particles (RLPs) reflect chylomicron remnants and very-low-density lipoprotein remnants, which are most likely to be atherogenic particles. To investigate the effect of thyroxine replacement on the metabolism of RLPs in hypothyroidism, we measured serum concentrations of RLPs during an oral fat-loading test in patients with hypothyroidism before and after thyroxine replacement. PATIENTS AND METHODS: Thirteen patients with hypothyroidism, having serum-free thyroxine (FT4) of 4.25 +/- 2.23 pmol/l (mean +/- SD) and TSH of 72.5 +/- 27.7 mU/l, participated in the study. Two-hundred grams of cream containing 32.9% of fat were given to each patient followed by blood draws every 2 h for 8 h. The patients became euthyroid after 3 months of T4 replacement, and the fat-loading tests were then repeated. RESULTS: Fasting levels of serum total cholesterol and low-density lipoprotein cholesterol were remarkably decreased after T4 therapy (P < 0.0005). Serum high-density lipoprotein cholesterol and triglyceride were also decreased by T4 therapy, not so remarkably but significantly (P < 0.05). Activities of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) increased 52% and 85%, respectively, from the pretreatment values. Serum concentrations of remnant-like particle cholesterol (RLP-C) and remnant-like particle triglyceride (RLP-TG), measured by immunoseparation assays, significantly decreased from 0.14 +/- 0.03 to 0.09 +/- 0.03 mmol/l (P < 0.0005) and from 0.19 +/- 0.11-0.11 +/- 0.07 mmol/l (P < 0.01), respectively. In the fat-loading test, serum low-density lipoprotein cholesterol concentrations were not changed, while serum RLPs concentrations were increased and remained high throughout the test, with the peak value at 6 h in a hypothyroid condition. In an euthyroid condition after T4 therapy, the peak values of RLPs were obtained at 4 h, and the concentrations were decreased rapidly. As the result, areas under the curve of serum RLPs were decreased remarkably after T4 therapy. CONCLUSIONS: Hypothyroidism seems to be associated with a decrease in metabolism of serum RLPs. Such altered metabolism of RLPs may be related to the decreased activities of LPL and HTGL and can be corrected by T4 replacement therapy.