Association of thyroid hormones with obesity and metabolic syndrome in Japanese children

Obesity is associated with health consequences, and thyroid dysfunction may be an adaption to the increased energy expenditure in obesity. With the rising prevalence of obesity in childhood, the prevalence of metabolic syndrome may also increase. In the current study, we have shown gender differences in the association of thyroid hormones with obesity, and attempted to elucidate the relationship between thyroid hormones and anthropometric parameters and biochemical data in obese Japanese children. We analyzed anthropometric measurements, blood pressure, body composition, thyroid hormones, and lipid profiles in 283 obese children. The association between thyroid hormones and several parameters differed by gender. The free T3 to free T4 ratio (fT3/fT4) in boys was negatively associated with the quantitative insulin sensitivity check index, whereas in girls, thyroid-stimulating hormone levels were positively correlated with levels of glucose, diastolic blood pressure, and non-high density lipoprotein-cholesterol, and fT3/fT4 was positively correlated with uric acid levels. FT3/fT4 in boys with metabolic syndrome was relatively higher than in those without metabolic syndrome. The cause of gender differences is unknown. Therefore, further studies with larger sample sizes and a long-term follow-up period are needed to address the influence of thyroid hormones on various parameters.     

肾病综合征患者血清甲状腺激素水平临床观察

目的：观察肾病综合征（NS）患者继发性甲状腺激素水平下降的发生率，并探讨其发病机制。方法：分别用全自动免疫分析仪和全自动生化分析仪检测52例中、重度水肿的NS患者治疗前后及22例原发性甲状腺功能减退症患者、18例健康者的血清FT3，FT4、促甲状腺激素（TSH）、总蛋白、白蛋白及尿总蛋白、白蛋白水平，并分析其血清甲状腺激素与血、尿蛋白间的相关性。结果：52例NS患者中41例甲状腺激素水平较正常值有不同程度下降，其中FT3为（1．72±0．59）pg／mL，FT4为（8．63±1．92）pg／mL，TSH（7．32±3．05）μIU／mL。NS组患者治疗前血清FT3与血清白蛋白水平呈正相关（r=0．387，t=2．523，P〈0．05），FT4与血清白蛋白水平呈正相关（r=0．359，t=2．369，P〈0．05），与尿蛋白（尿总蛋白及尿白蛋白）间无相关性：TSH与血清白蛋白及尿蛋白间无相关性。结论：中、重度水肿的NS患者易出现继发性甲状腺激素水平下降，甲状腺激素改变水平与血清白蛋白水平相关。     

糖尿病患者下丘脑-垂体-甲状腺功能临床观察

目的 :观察糖尿病患者下丘脑 垂体 甲状腺功能改变。方法 :检测 5 4例糖尿病患者血糖、甲状腺激素水平及TSH对TRH兴奋试验的反应。结果 :5 4例患者中 2 1例呈低T3血症 ,其中 3例伴有T4水平下降 ,2例伴FT3、FT4下降 ,但T4水平正常。TRH兴奋试验均正常。低T3血症组患者空腹血糖值与基础T3(r=- 0 .5 33,P <0 .0 5 )、基础TSH(r=- 0 .4 88,P <0 .0 5 0 )呈负相关。结论 :糖尿病患者在控制不良或合并严重并发症时呈现低T3综合征 ,但垂体 甲状腺轴的功能正常。检测甲状腺激素水平有助于糖尿病病情及预后的估计。     

甲状腺激素对大鼠额叶乙酰胆碱的影响

目的研究成年期甲状腺功能减退症大鼠额叶内乙酰胆碱变化及甲状腺素替代治疗后的情况。方法 26只成年期雄性SD大鼠随机分为三组,用丙基硫氧嘧啶(PTU)建立成年期大鼠甲减模型,采用放射免疫法测定健康对照组、甲减组、甲状腺素替代治疗组(T4-6)大鼠的血清甲状腺激素水平;碱性羟胺比色法测定脑组织乙酰胆碱含量;用单因素方差分析比较三组之间各项指标差异。结果与健康对照组相比,甲减组大鼠血清T3、T4水平显著减低、TSH水平增加(P<0.05);替代治疗后,血清T3、T4、TSH恢复至正常水平;甲减组大鼠额叶内乙酰胆碱含量降低(P<0.05),替代治疗后乙酰胆碱含量与对照组相比差异无统计学意义(P>0.05)。结论成年期甲减大鼠额叶内乙酰胆碱含量减少,甲状腺素替代治疗后乙酰胆碱含量恢复正常。     

Pseudo-central hypothyroidism

Central hypothyroidism is an exceedingly rare form of hypothyroidism that results from a variety of conditions affecting the hypothalamus and the pituitary gland. The classic biochemical abnormality seen in these patients includes a low serum level of circulating thyroxine (T4) concomitant with an inappropriately low level of thyrotropin. Because patients with isolated triiodothyronine (T3) toxicosis also present with this biochemical pattern, it is important to measure T3 levels in such patients before making a diagnosis of central hypothyroidism.     

Thyroid hormone resistance

General resistance to the action of thyroid hormones is characterized by increased levels of thyroid hormones and normal thyroid hormone binding proteins but clinical euthyroidism. There is a wide clinical spectrum ranging from patients with congenital goitre and signs of subclinical hypothyroidism to subjects with no physical abnormality. In the most affected patients special physical features have been described. Serum thyrotrophin (TSH) and the response to thyrotrophin releasing hormone (TRH) is mostly normal but may fluctuate being at times elevated and even markedly increased values may be encountered. Studies on lymphocytes and fibroblasts indicate that a decreased affinity of thyroid hormones for nuclear receptors, a decreased binding capacity of the receptors or some post-receptor mechanism may be responsible for these changes. Hitherto, six families, comprising 24 patients and seven single cases, have been described. The pedigrees are compatible with dominant inheritance. Selective refractoriness of the pituitary thyrotrophs to thyroid hormones has been described in five patients with hyperthyroidism. Excessive secretion of TSH is the cause of hyperthyroidism. In four of the cases reported TRH caused an exaggerated TSH response and TSH was partially suppressible by additional exogenous thyroid hormone. The response of TSH and the behaviour of the alpha- and beta-subunits of TSH distinguish this syndrome from TSH-induced hyperthyroidism due to pituitary tumours. The underlying mechanisms are unknown.     

Type 3 deiodinase is critical for the maturation and function of the thyroid axis

Developmental exposure to appropriate levels of thyroid hormones (THs) in a timely manner is critical to normal development in vertebrates. Among the factors potentially affecting perinatal exposure of tissues to THs is type 3 deiodinase (D3). This enzyme degrades THs and is highly expressed in the pregnant uterus, placenta, and fetal and neonatal tissues. To determine the physiological role of D3, we have generated a mouse D3 knockout model (D3KO) by a targeted inactivating mutation of the Dio3 gene in mouse ES cells. Early in life, D3KO mice exhibit delayed 3,5,3'-triiodothyronine (T3) clearance, a markedly elevated serum T3 level, and overexpression of T3-inducible genes in the brain. From postnatal day 15 to adulthood, D3KO mice demonstrate central hypothyroidism, with low serum levels of 3,5,3',5'-tetraiodothyronine (T4) and T3, and modest or no increase in thyroid-stimulating hormone (TSH) concentration. Peripheral tissues are also hypothyroid. Hypothalamic T3 content is decreased while thyrotropin-releasing hormone (TRH) expression is elevated. Our results demonstrate that the lack of D3 function results in neonatal thyrotoxicosis followed later by central hypothyroidism that persists throughout life. These mice provide a new model of central hypothyroidism and reveal a critical role for D3 in the maturation and function of the thyroid axis.     

Hoffmann syndrome presenting to the emergency department]

We report a case of hypothyroid myopathy, or Hoffmann syndrome, in a 31-year-old man who presented to the emergency department with asthenia, muscular pain, cramps, and joint pain. Tests revealed increased creatine phosphokinase level (8102 U/L) and severe hypothyroidism (content of T4=3.8 pg/ml, T3=1.3 pg/ml, and thyrotropin stimulating hormone>150 microU/ml). Other causes of myopathy were excluded by anamnestic investigation and paraclinical exam. Treatment was begun with thyroid hormones (from 75 to 175 microg) and good clinical evolution was rapid. The pathophysiology of hypothyroid myopathy, clinical aspects and pathologic anatomic elements are described. The exact etiology of hypothyroidism must be known because some pathologic features are benign and treatment can have good results, whereas others, such as cancer, have worse prognosis.     

Resistance to the effects of thyroid hormone in children

We have described three children with serum levels of TSH that are too high for the concomitant serum T4 level. Two of them meet the criteria for combined central and peripheral resistance to thyroid hormone. The third has long-standing central resistance to TSH suppression previously reported in congenital hypothyroidism. The recognition of this syndrome by physicians is important to avoid unnecessary and potentially dangerous treatment.     

TSH may not be a good marker for adequate thyroid hormone replacement therapy

The objective of this study was to evaluate parameters of thyroid function and indices of peripheral thyroid hormone action (such as SHBG) in patients whose hypothyroidism was considered well controlled under current criteria. Eighty-five patients with T4-treated hypothyroidism, 28 of whom had athyria, were compared with 114 normal individuals with the same TSH levels. T3 levels were significantly lower in hypothyroidism although mean T4 and fT4 levels were significantly higher. Furthermore, mean SHBG levels were significantly lower in hypothyroidism independently of age. The difference remained when stricter criteria for adequate treatment were applied (TSH < 2.5 microgU/ml). Significant negative correlations were found between logTSH and T3. The slopes of the regression lines of T3 to TSH were significantly different in the control group and the hypothyroid group: thus, for the same TSH levels, T3 levels were lower in the hypothyroid group. We conclude that patients with T4-treated hypothyroidism have lower T3 levels, lower T3/T4 ratio and lower SHBG than normal individuals with the same TSH, perhaps indicating relative tissue hypothyroidism in the liver. TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues. The co-administration of T3 may prove more effective in this respect, provided novel suitable preparations are developed. Until this is accomplished, substitution in hypothyroidism should aim at low normal TSH, to ensure normal T3 levels.     

危重症患儿甲状腺功能测定及其意义

为进一步研究危重症患儿垂体甲状腺功能与疾病预后关系，检测３１例重危症患儿血清甲状腺激素水平并与２０例健康儿童作对照观察。结果：重危症患儿低三碘甲腺原氨酸（Ｔ３）和（或）低甲状腺素（Ｔ４）者２８例（８７．５％），以低Ｔ３发生率最高。６例出现低Ｔ３伴低Ｔ４者中有５例死亡。重危症患儿死亡组Ｔ４（３８．１４±８．４８ｎｍｏｌ／Ｌ）明显低于存活组（８２．５５±３７．８６ｎｍｏｌ／Ｌ）。认为：检测重危患儿血清甲状腺激素对正确判断甲状腺功能及估计疾病预后有一定价值     

Enhanced prolactin secretion in patients with primary hypothyroidism during thyroid replacement

Thyroid hormones are known to exert some influence on prolactin (PRL) secretion indirectly via the hypothalamic dopaminergic system and directly at the level of pituitary gland. In order to study the effect of thyroid hormones on the activity of hypothalamic dopamine neurons, lactotrophs and thyrotrophs, we administered increasing doses of thyroid hormones to patients with primary hypothyroidism, and examined the changes of basal PRL, TSH and PRL responses to a dopamine receptor blocker (sulpiride). Among 24 patients with primary hypothyroidism, hyperprolactinemia was observed in 10 cases (18.0-236 ng/ml, mean +/- S.E. 58.6 +/- 20.0 ng/ml), while elevated TSH levels were observed in all of them (6.6-972 microU/ml, mean +/- S.E. 231.4 +/- 53.9 microU/ml). There was a significant negative relationship between plasma T3 or T4 levels and basal plasma TSH levels (p less than 0.05), whereas a poor correlation was observed between the thyroid hormones and basal plasma PRL levels (r = -0.25, p greater than 0.05). Following the administration of gradually increasing doses of thyroid hormones, plasma PRL showed paradoxical and transient increases, while plasma TSH decreased steadily. Plasma PRL response to sulpiride also became exaggerated during the treatment. The elevated basal PRL level and the enhanced response to sulpiride turned to be within the normal range when the patients became euthyroid by treatment. These results may indicate that thyroid hormones stimulate not only hypothalamic dopaminergic activity, but also the lactotroph activity in a long term hypothyroid state. Regarding the paradoxical elevation of basal PRL, one can postulate that the activation of lactotroph by a small dose of thyroid hormone may be able to overcome the hypothalamic dopaminergic inhibition.     

Thyroid function after subtotal resection for hyper-thyroidism: a prospective study

B.KÅGEDAL¹
Abstract. Eight-seven patients treated for thyrotoxicosis by subtotal thyroidectomy were examined 6 weeks, 6 months and 12 months after surgery. Thirty-six of the patients were also examined 24 months after surgery.
The patients were divided into two groups according to serum concentration of thyrotrophin (TSH) 6 weeks after surgery. Group I contained fifty-five patients with a normal serum TSH, of whom three developed recurrent hyperthyroidism during the observation period. The remaining fifty-two patients were clinically euthyroid during the entire observation period but had rather low serum thyroxine (T4) levels and normal serum triiodothyronine (T3) levels 6 weeks after surgery. Most patients had a normal TSH response to thyro-trophin-releasing hormone (TRH). T4 levels rose significantly within 6 months after surgery and then remained almost unchanged.
Group II contained thirty-two patients with a serum TSH above 5 mU/1 6 weeks after surgery. Seven of these patients developed hypothyroidism within 1 year of surgery. The twenty-five remaining patients had low serum T4 with normal serum T3 levels at 6 weeks. TSH response to TRH was pathologically raised. Basal TSH level remained raised during the observation period but serum T4 levels approached those in group I within 12 months.
These investigations show that patients with a raised basal serum TSH are at risk of developing hypothyroidism. Normal serum concentrations of thyroid hormones are reached sooner by patients with normal TSH levels than by patients with raised TSH levels. The basal serum TSH level seems to be a better indicator of risk of hypothyroidism than the serum T4 level, which is low in most patients 6 weeks after surgery.     

Classification of hypothyroidism in evaluating patients after radioiodine therapy by serum cholesterol, T3-uptake. Total T4, FT4-index, total T3, basal TSH and TRH-test

Abstract. During a follow-up examination of patients after radioiodine therapy for thyrotoxicosis, 128 patients without recurrent hyperthyroidism were investigated for the clarification of different degrees of hypothyroidism. The clinical diagnosis and the conventional tests for circulating thyroid hormones were compared to the estimation of serum thyroid stimulating hormone (TSH), and to the thyrotropin-releasing hormone (TRH) test, which was performed with 500 μg synthetic TRH I.V., and referred to age and sex specific normal ranges. Moreover, serum triiodothyronine (T₃) was estimated by radioimmunoassay. Results: 1. A gradual classification of biochemical group-differences gave more significant discrimination than a division into groups based on clinical impression. Different grades of severity of hypothyroidism could be demonstrated by highly significant differences of free thyroxine index (FT₄-Index) between the 1st group of patients with low FT₄-Index and a 2nd group with raised basal TSH (and normal FT₄-Index), between the 2nd group and a 3rd group with an elevated value of Δ TSH_max (and normal FT₄-Index and basal TSH), and between the 3rd group and a 4th group of biochemically normal reacting patients and controls. There was a less significant difference with very considerable overlap between clinically established groups. 2. T₃-uptake, total T₄ and FT₄-Index are not sufficient for detecting hypothyroidism in individual patients, although their group-differences are significant in biochemical classification. 3. Neither between clinical nor between biochemical groups was there any significant correlation with serum cholesterol. 4. Triiodothyronine can be normal or elevated in a situation with low T₄ and raised TSH concentrations. Conclusions: Evidence could be given that hypothyroidism is a graded phenomenon. Its classification by biochemical data is more reasonable than a clinical division. Advancing severity of hypothyroidism after radiation therapy is compensated during a certain period by supplementary production of triiodothyronine. As thyroid hormone concentration in patients with pathological serum TSH or TRH-test is significantly lower than in euthyroid patients or in controls, replacement therapy in early stages of hypothyroidism also seems reasonable.     

Thyroid functions in patients treated with interleukin-2 and lymphokine-activated killer cells.

Treatment of malignant disease with interleukin-2 and lymphokine-activated killer cells activates autoreactive T lymphocytes, stimulates release of cytokines and induces expression of HLA-class II antigens by tumour cells. We studied eight patients with hepatocellular carcinoma treated with a total of 16 courses of recombinant human interleukin-2 and lymphokine-activated killer cells and observed them for features of autoimmune thyroid disease. During the course of treatment there were significant decreases in total serum T4 and T3 and free thyroxine levels, but no change in TSH levels when all patients were analysed as a group. This was due to a number of factors including suppression of thyroid hormone release, haemodilution during interleukin-2 infusion and actual removal of thyroid hormones from the circulation during leukapheresis. Thyroid hormones returned to normal levels during resting period. One patient subsequently developed compensated hypothyroidism (normal total T4, total T3 and free T4 but elevated TSH) and four patients had features of 'sick euthyroid syndrome' (low total T4, total T3 or free T4 but normal TSH). None of the patients studied developed antibodies to thyroglobulin or microsomes. In contrast, no abnormality of thyroid function was seen in any of the nine subjects who received no active treatment. In conclusion, thyroid dysfunction was associated with immunotherapy of malignant disease with interleukin-2 and lymphokine-activated killer cells. This may arise from direct hormonal effects of the cytokines on thyroid hormone production.     

Free thyroxine estimation for the screening of hyper- and hypothyroidism in an adult population

Serum free thyroxine (FT4), total T4 (T4) and total T3 (T3) were determined by radioimmunoassay in 1,114 adults during a periodic health evaluation to detect unsuspected thyroid dysfunction. As a result, 3 patients with hyperthyroidism, 4 with hypothyroidism, 3 taking thyroid medication, 4 with chronic thyroiditis, 1 with simple goiter and 3 women under estrogen administration were found. Free T4 values were within the normal limits in the present four subjects taking estrogens, but all of them showed high T4 and one high T3 values. FT4 and T4 were low in four patients with hypothyroidism, but two of them showed normal T3 values. For the screening of hyperthyroidism, FT4 was the most reliable measurement and determination of either FT4 or T4 was suitable for the screening of hypothyroidism, but T3 measurement did not diagnose all patients with hypothyroidism, but T3 measurement did not diagnose all patients with hypothyroidism.     

Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of current evidence, should be treated with appropriate replacement therapies

This article documents the role of hypothalamic hypothyroidism and decreased T4-->T3 conversion as the cause of low T4 and T3 in non-thyroidal illness syndrome (NTIS). This article also presents the arguments for administration of replacement triiodothyronine (T3) and thyroxine (T4) hormone in patients who have NTIS. It is impossible to be certain at this time that it is beneficial to replace hormone, or whether this could be harmful. Only a prospective study will be adequate to prove this point, and probably this would need to involve hundreds of patients. If effective, thyroid hormone replacement will be one of many beneficial treatments given the patient, rather than a single magic bullet, which would reverse all the metabolic changes going wrong in these severely ill patients.