Optimum replacement dose of thyroid hormone assessed by highly sensitive TSH determination in patients with congenital hypothyroidism

Serum thyroid hormone concentrations were measured in 100 samples from 25 patients with congenital hypothyroidism who were clinically well while receiving L-T4 therapy. Thyroxine concentrations were significantly higher than those of controls (p less than 0.01), while triiodothyronine was not significantly different. These samples were divided into four groups according to serum thyroid stimulating hormone concentrations as measured by highly sensitive immunoradiometric assay (IRMA-TSH). Serum thyroid hormone concentrations were compared among groups. The replacement dose of L-T4 and serum thyroid hormone in groups with undetectable IRMA-TSH were significantly higher than those in groups with normal or increased IRMA-TSH. These results show that serum thyroxine concentrations increase in most patients with congenital hypothyroidism on L-T4 therapy. Therefore, thyroxine concentrations above normal are not necessarily of clinical significance if IRMA-TSH is detectable. Undetectable IRMA-TSH might indicate the necessity for a reduction in the L-T4 replacement dose in patients with congenital hypothyroidism.     

Sub-clinical hypothyroidism in infertile Nigerian women with hyperprolactinaemia

Studies on the impact of subclinical hypothyroidism in infertility are scarce and this seeks to determine the proportion of infertile Nigerian women with hyperprolactinaemia that had subclinical hypothyroidism. Serum prolactin and thyroid stimulating hormone were determined using ELECSYS 1010 auto analyzer. Two hundred infertile women were evaluated and 67(33.7%) had hyperprolactinaemia. Subclinical hypothyroidism was observed in 14.9% of women with hyperprolactinaemia, 4.5% and 10.5% of women with primary and secondary infertility, while hyperprolactinaemia was observed in 29.9% and 70.1% in primary and secondary infertility respectively. Mean levels of thyroid stimulating hormone and prolactin were higher in secondary infertility than primary infertility. Subclinical hypothyroidism and hyperprolactinaemia were higher in secondary infertility than primary infertility. The ratio of proportions between hypothyroidism and hyperprolactinaemia was 1:7. Keywords: Sub clinical hypothyroidism, Hyperprolactinaemia, Primary infertility, Secondary infertility.     

A case of hypothyroidism with simultaneous presence of stimulating type anti-thyrotropin (TSH) receptor antibodies and anti-thyroxine (T4) autoantibodies.

We have examined a hypothyroid patient with stimulating type anti-thyrotropin (TSH) receptor antibodies and without blocking type anti-TSH receptor antibodies. Although she had high serum TSH (240 microU/ml) and low free triiodothyronine (FT3, 0.49 pg/ml) concentrations, which agree with physical findings of hypothyroidism, she had an unusually high free thyroxine (FT4) concentration (3.56 ng/dl). Incubation of her serum with 125I-T4, followed by precipitation with 12.5% polyethylene glycol (PEG) disclosed a higher binding of 125I-T4 (34.4%) than in normal controls, being 5-7%. In addition, binding of 125I-T4 to her serum gamma-globulin was completely displaced by the addition of unlabelled T4. From these results it was concluded that her serum contained anti-T4 autoantibodies. Treatment with synthetic T4 was begun and her thyroid function was monitored by sensitive TSH radioimmunoassay (RIA) and RIA of FT4 after PEG treatment. Since both sensitive TSH RIA and FT4 RIA results after PEG treatment give results concordant with the physical findings, it was concluded that both of the RIA results are useful for the evaluation of thyroid function in patients with thyroid hormone autoantibodies.     

Comparative effects of desiccated thyroid gland and sodium salt of L-thyroxine in the treatment of hypothyroidism

The studies comparing the actions of dried thyroid gland (Thyroideum-Polfa) with L-thyroxine sodium (L-T4) were carried out in 20 female patients with hypothyroidism, including 19 patients with the primary hypothyroidism and 1 patient with hypothyroidism secondary to pituitary deficiency. Administration of the dried thyroid gland did not normalize blood serum T4 an TSH in any patient. Normal serum T4 or even slightly increased was achieved in all patients treated with L-T4. Serum TSH was normalized in 17 patients with the primary hypothyroidism. The following conclusions have been drawn: 1. Dried thyroid gland (Thyroideum-Polfa) is ineffective in the treatment of hypothyroidism. 2. Serum TSH remains elevated despite normal serum T3 in cases of the primary hypothyroidism with decreased serum T4 levels. 3. Sodium salt of L-thyroxine should be used for the treatment of hypothyroidism. 1-Triiodothyronine sodium may be used as an adjuvant therapy.     

Grades of Hypothyroidism

Seventy-nine patients with hypothyroidism and autoimmune thyroid disease were studied, and allotted to one of four categories on the basis of clinical and biochemical features. Firstly, patients with overt hypothyroidism had obvious clinical features of hypothyroidism and abnormal results from routine tests of thyroid function. Secondly, those with mild hypothyroidism, however, had minor and non-specific symptoms, but the routine measurements of circulating thyroid hormone concentration generally lay within the normal range, although they were significantly lower than those seen in subclinical hypothyroidism or in normal subjects. The serum concentration of thyroid-stimulating hormone (TSH) was raised in this group and their symptoms resolve with treatment. Thirdly, patients with subclinical hypothyroidism were asymptomatic, had a raised serum TSH concentration, but all other measurements of thyroid function are indistinguishable from those recorded in people with autoimmune thyroid disease without disturbance of thyroid function and in normal subjects. Lastly, subjects with circulating thyroid antibodies, normal indices of thyroid function, and a normal serum TSH concentration were indistinguishable biochemically from normal subjects.Thus hypothyroidism is a graded phenomenon, the most valuable features for defining the individual grade being the clinical manifestations, the serum TSH concentration, and the presence of circulating antibodies to thyroid tissue.     

Screening for thyroid disease in a primary care unit with a thyroid stimulating hormone assay with a low detection limit.

In a study at a primary care centre in a predominantly rural area of Sweden the records of all patients with established thyroid disease were scrutinised and 2000 consecutive adult patients screened with an immunoenzymometric thyroid stimulating hormone assay. The aims of the study were fourfold: firstly, to assess the total burden of thyroid disease in primary care centres in Sweden; secondly, to assess the efficacy of clinical diagnosis of the disease in unselected populations of patients; thirdly, to assess the efficacy of clinical evaluation of treatment with thyroxine; and, lastly, to see whether a single analysis of the serum thyroid stimulating hormone concentration by recent methods would be enough to identify an abnormality of thyroid function. Of the roughly 17,400 adults in the study community, 111 women and 10 men were being treated for thyroid disease. Screening detected 68 patients (3.5%) not receiving thyroxine who had a serum thyroid stimulating hormone concentration of 0.20 mU/l or less, all of whom were followed up clinically. Fifty of these patients were also studied biochemically during follow up. Only nine of the 68 patients had thyroid disease (three with thyrotoxicosis requiring treatment), no evidence of the disease being found in the remainder. Sixteen patients had spontaneous hypothyroidism requiring treatment, and neither these nor three patients with thyrotoxicosis had been detected at the preceding clinical examination. Of 35 patients in whom thyroid disease was suspected clinically at screening, none had laboratory evidence of thyroid dysfunction. In this series 1.3% of all women in the study community (2.6% of all 50-59 year olds) and 0.1% of the men were being treated for thyroid disease at the primary care centre, roughly 1.0% of adults subjected to screening were found to have thyroid disease requiring treatment, and most patients with a thyroid stimulating hormone concentration of 0.20 mU/l or less did not have thyroid dysfunction. It is concluded that measuring the basal serum thyroid stimulating hormone concentration by present methods is insufficient for the biochemical assessment of thyroid dysfunction in unselected populations.     

Transient neonatal hyperthyrotrophinaemia: a serum abnormality due to transplacentally acquired antibody to thyroid stimulating hormone.

In a screening programme for neonatal hypothyroidism an otherwise healthy female infant was found to have a high concentration of thyroid stimulating hormone in a filter paper blood spot and in serum. A high concentration was also found in the maternal serum. Mother and baby were both biochemically euthyroid with normal serum thyroxine concentrations. The apparently high concentration of thyroid stimulating hormone in the mother was due to the presence of an IgG antibody that bound to human but not bovine thyroid stimulating hormone. Maternal serum inhibited the action of human thyroid stimulating hormone in an in vitro bioassay for the hormone. It is suggested that the baby acquired the antibody transplacentally, especially as the concentration of thyroid stimulating hormone subsequently fell. It is concluded that maternal serum should be assayed for thyroid stimulating hormone when a neonate is found to have a high concentration of the hormone and a normal concentration of thyroxine to establish the incidence of this finding and to avoid inappropriate replacement treatment.     

Growth,development, and reassessment of hypothyroid infants diagnosed by screening.

Thirty]six neonates in whom hypothyroidism was diagnosed after thyroid stimulating hormone screening were reassessed at 1 year. All had grown satisfactorily and the mental development scores were normal in all except two. Treatment was withdrawn in 32 and persistent hypothyroidism was confirmed in 31 cases. Thyroid stimulating hormone concentrations were raised in one-third of cases before the withdrawal of treatment and this was associated with generally lower concentrations of serum thyroxine (T4) and smaller doses of L-thyroxine than in those cases with normal concentrations of thyroid stimulating hormone. In treating congenital hypothyroidism, serum T4 concentrations should be monitored regularly and the dose of thyroxine adjusted to maintain serum T4 in the upper part of the reference range.     

Neonatal screening for congenital hypothyroidism by measurement of plasma thyroxine and thyroid stimulating hormone concentrations.

Neonatal screening for congenital hypothyroidism was introduced in the City of Birmingham in 1980 by measuring concentrations of both thyroid stimulating hormone and thyroxine in plasma. Over two years 30 108 babies were tested. Thirty one babies were recalled because of thyroid stimulating hormone concentrations greater than 40 mU/l, of whom 12 were treated with replacement thyroxine. Six babies were found to have low thyroxine concentrations because of reduced thyroxine binding globulin and five raised thyroxine values because of increased thyroxine binding globulin. As a result of this study screening was continued with measurement of thyroid stimulating hormone only as the primary test for congenital hypothyroidism, the thyroxine value being measured only when the concentration of thyroid stimulating hormone exceeded 20 mU/l.     

A case of Graves' disease with false hyperthyrotropinemia who developed silent thyroiditis.

We encountered a patient who developed silent thyroiditis during the course of Graves' disease. The diagnosis of silent thyroiditis was made on the basis of a low thyroidal 131I uptake, no response to the thyrotropin releasing hormone (TRH) test, and subsequent hypothyroidism despite the presence of high titers of thyrotropin (TSH) receptor antibody (TRAb) and thyroid stimulating antibody (TSAb). The patient, in addition, had a discrepancy between serum TSH and thyroid hormone values. This was due to the presence of interfering substances that react to mouse IgG in the sera since serum TSH levels were decreased in a dose dependent manner by the addition of increasing amounts of mouse IgG to the sera. It should therefore be noted that silent thyroiditis can develop in patients with Graves' disease. Furthermore, clinicians should be aware that two-site immunoassay kits that use mouse monoclonal antibodies are subject to interference by some substances, possibly antibodies which react to mouse IgG.     

Hypothyroidism in reproductively inhibited prairie deer mice (Peromyscus maniculatus bairdi) from laboratory populations

Several thyroid function parameters were compared between reproductively inhibited prairie deer mice of both sexes taken from laboratory populations and corresponding reproductively capable controls. The results of these experiments indicated the following: 1) prairie deer mice females had a statistically significant daily variation in mean serum thyroxine concentration and males displayed a similar trend; 2) total serum thyroxine and triiodothyronine were significantly lower in both male and female reproductively inhibited population animals compared with reproductively capable controls; 3) several morphometric characteristics of the thyroid of male and female population prairie deer mice were significantly different from that of control males and females, suggesting functional hypothyroidism in both sexes; 4) thyroid histology of male population deer mice was different from that of female population animals. In males, the data suggested that thyroid-stimulating hormone (TSH) stimulation was deficient due to some undetermined secondary hypothyroidism. In females, reduced serum thyroxine and triiodothyronine concentrations were observed due to primary hypothyroidism of unknown origin. The interrelationship between thyroid and adrenal function is discussed here and it is concluded that each of the systems may contribute to the observed reproductive inhibition. In particular, it was noted that the mechanism of response between population males and females may be quite different. No conclusive data are available to suggest whether one or the other system is the primary controller of the reproductive inhibition.     

Graves' ophthalmopathy and subclinical hypothyroidism: diagnostic value of the thyrotropin releasing hormone test.

Five patients with Graves'' ophthalmopathy and no previously documented clinical or laboratory evidence of hyperthyroidism were studied. Their serum levels of thyroxine and triiodothyronine (T3) and their T3 uptake were normal. Although the baseline serum level of thyrotropin (TSH) was normal in two patients, it was increased on the other three, and when TSH releasing hormone (TRH) was administered the T3 response was impaired in three patients and the TSH response was exaggerated in all five. These findings facilitated the diagnosis of subclinical hypothyroidism and distinguished the patients from those with Graves'' ophthalmopathy and normal thyroid function or subclinical hyperthyroidism. Thyroid antibodies were detected in the serum of four of the five patients, suggesting the coexistence of chronic autoimmune thyroiditis; this disorder could account in part for the subclinical hypothyroidism, which was even present in the two patients in whom thyroid-stimulating immunoglobulin was found in the serum. These observations indicate the value of a TRH stimulation test in detecting subclinical hypothyroidism in patients with Graves'' ophthalmopathy who appear from clinical and routine laboratory studies to have normal thyroid function but could have normal function or subclinical hyperthyroidism.     

Transient neonatal hypothyroidism due to transplacental transfer of maternal immunoglobulins that inhibit TSH binding, TSH-induced cAMP increase and cell growth

Transient neonatal hypothyroidism due to transplacental transfer of maternal blocking type TSH receptor antibodies (TRAb) was found in a baby born to a 27-yr-old mother, who had been receiving thyroxine medication for primary myxedema. Maternal IgG inhibited radiolabelled TSH binding to its receptor (TBII), TSH-stimulated thyroid adenylate cyclase (AC) activation (TSII) and TSH-stimulated 3H-thymidine uptake (TGII) in cultured rat thyroid cells (FRTL-5). At birth, the baby's IgG showed similar activities to maternal IgG but all these activities decreased gradually, and disappeared from her serum within 12 weeks of age. In the baby, initially nonvisualized thyroid was clearly visualized on 99 m-Tc thyroid scintigraphy when all these blocking activities disappeared, TSII and TGII being decreased more slowly than TBII, and the baby remained euthyroid after discontinuation of thyroxine. This study suggests that such IgGs induced hypothyroidism and thyroid atrophy in the mother and were responsible for transient neonatal hypothyroidism in the baby.     

Measurement of serum thyroxine binding prealbumin in various thyroidal states by radioimmunoassay

Serum thyroxine binding prealbumin (TBPA) levels in various thyroidal states were examined by radioimmunoassay (RIA). This technique is highly sensitive, accurate and reproducible. The normal mean (+/- 2SD) level of serum TBPA is 26.9 +/- 8.0 mg/dl (29.4 +/- 5.2 in men and 24.9 +/- 7.6 mg/dl in women). Serum TBPA levels in pregnant women were significantly lower than in normal females (P less than 0.05). Serum TBPA levels in patients with untreated hyperthyroidism were 12.9 +/- 4.0 mg/dl (mean +/- SD) and in patients with untreated hypothyroidism were 25.2 +/- 4.7 mg/dl (mean +/- SD). The mean TBPA concentrations in untreated hyperthyroidism were significantly lower than that for normal population (P less than 0.01), but untreated hypothyroidism was almost within normal range. The changes in TBPA levels in hyperthyroidism and hypothyroidism were similar to those in TBG levels. In untreated hyper- and hypothyroidism, restoration to euthyroidism by treatment was uniformly accompanied by a normalization of serum TBPA and TBG levels. A negative correlation between serum thyroid hormone binding protein (TBG and TBPA) and free thyroxine was observed in patients with hyperthyroidism. The coefficient of correlation between TBPA and free thyroxine was -0.80 (P less than 0.01) and between TBG and free thyroxine -0.58 (P less than 0.01). From these experiments it appears that not only TBG but also TBPA may play an important role in the regulation of the free thyroxine concentration in response to various thyroidal states.     

Graves' disease: immunological and immunogenetic indicators of relapse

The use of measurements of antibody to the thyroid stimulating hormone receptor and HLA-DR3 phenotype for predicting relapse of hyperthyroidism in patients with Graves'' disease receiving medical treatment is controversial. Fifty eight new patients with Graves'' disease were followed up prospectively for up to 96 months after treatment with antithyroid drugs for 12 months. The presence of antibody to the thyroid stimulating hormone receptor before the start of treatment, measured as immunoglobulins inhibiting binding of thyroid stimulating hormone, was not associated with relapse. Patients who remained positive for antibodies after treatment tended to relapse within six months, but no relation with long term relapse was found. HLA-Cw7 but not HLA-DR3 was significantly associated with relapse. The presence of HLA-DR4 was significantly associated with remission and with absence of antibodies to thyroid stimulating hormone receptor. HLA-DR4 may therefore protect against relapse of thyrotoxicosis by immunomodulation triggered by antithyroid drugs, which results in the synthesis of antibodies to the thyroid stimulating hormone receptor being inhibited.     

Clinical importance of reversibility in primary goitrous hypothyroidism.

Twenty seven hypothyroid patients with a serum concentration of thyroid stimulating hormone (TSH) of over 40 mU/1 were followed up for three to 20 weeks without replacement therapy. The serum thyroid hormone concentrations increased with a dramatic decrease in serum TSH values in 14 patients (reversible group) but there was no significant change in the other 13 (irreversible group). Fourteen out of 19 patients with goitre but none of the eight patients without goitre belonged to the reversible group. All of the 11 patients with a high uptake of iodide by the thyroid, three of the six with a normal uptake, and none of the 10 with a low uptake belonged to the reversible group. These observations indicate that patients with goitrous hypothyroidism with a preserved thyroid uptake of iodide are likely to become euthyroid spontaneously without replacement therapy.     

Reduced serum free thyroxine concentration in postmenopausal women receiving oestrogen treatment.

Thyroid hormone state was assessed in a group of postmenopausal women who had received long term treatment with oestrogen. Serum concentrations of total thyroxine, triiodothyronine, and thyroxine binding globulin were raised compared with those in a control group given placebo; serum concentrations of thyroid stimulating hormone did not differ between the groups. Oestrogen treatment resulted in a significant decrease in the serum free thyroxine concentration and in the ratio of thyroxine to thyroxine binding globulin, which supports the view that oestrogen is the causative factor of the physiological reduction in free thyroid hormone during pregnancy.     

Thyroid dysfunction in adult long-term survivors after hemapoeitic stem-cell transplantation (HSCT).

Thyroid function was evaluated in 72 adult survivors (41 females and 31 males) at 16 to 56 years of age, 1.5 years mean time (range 0.2 - 9.8) after hemapoeitic stem cell transplantation (HSCT) with no known prior history of thyroid dysfunction. Thyroid stimulating hormone (TSH) and free thyroxin levels (FT4) were determined before and after stimulation with thyrotropin releasing hormone (TRH). Conditioning regimens for HSCT did not include TBI. Overt hypothyroidism (basal TSH > 8 microIU/ml, FT4 < 0.8 ng/dl) was observed in 6% of male patients and 5% of female patients; subclinical hypothyroidism (basal TSH 4 - 8 microIU/ml, low normal FT4 0.8 - 1.9 ng/dl) was observed in 13% of males and 5% of females. A significant number of euthyroid patients (40% males and 54% females) with normal basal TSH and FT4 levels overresponded to TRH stimulation; the finding being statistically significant (p < 0.005). A heavy TSH response after TRH stimulation indicates compensated subclinical dysfunction of the thyroid gland. Chemotherapy-only conditioning regimens may have an adverse effect on thyroid gland function not always detected by determination of basal TSH and FT4 levels. This finding warrants long-term evaluation of thyroid function in HSCT patients.     

Effects of variations in thyroid hormone serum concentrations on serum ACE-activity

Serum angiotensin converting enzyme activities were significantly increased in 26 untreated hyperthyroid patients (20.3 +/- 5.4 U/ml; P less than 0.001) compared with healthy control subjects (13.1 +/- 2.3 U/ml). In 12 patients a significant fall in enzyme activities was observed after treatment compared with pretreatment serum ACE levels (P less than 0.001). Eight patients with hypothyroidism (15.7 +/- 5.1 U/ml) and 11 athyreotic patients, totally thyroidectomized for well-differentiated thyroid cancer, showed no significant differences in serum ACE activities (14.3 +/- 2.2 U/ml) compared with control subjects. After thyroid hormone supplementation a significant increase in serum ACE activity (P less than 0.05) was found in the athyreotic patients. Addition of increasing amounts of L-thyroxine to a serum sample of an athyreotic patient showed no significant effect on ACE activity in vitro. We suggest that the elevated serum ACE activity in hyperthyroidism is not from the thyroid gland, but represents a direct effect of thyroid hormone on ACE synthesis and/or release from endothelial cells.     

Selenium and its relationship with selenoprotein P and glutathione peroxidase in children and adolescents with Hashimoto’s thyroiditis and hypothyroidism

The essential trace element selenium (Se) is required for thyroid hormone synthesis and metabolism. Selenoproteins contain selenocysteine and are responsible for biological functions of selenium. Glutathione peroxidase (GPx) is one of the major selenoproteins which protects the thyroid cells from oxidative damage. Selenoprotein P (SePP) is considered as the plasma selenium transporter to tissues. The aim of this study was to evaluate serum Se and SePP levels, and GPx activity in erythrocytes of children and adolescents with treated Hashimoto’s thyroiditis, hypothyroidism, and normal subjects.Blood samples were collected from 32 patients with Hashimoto’s thyroiditis, 20 with hypothyroidism, and 25 matched normal subjects. All the patients were under treatment with levothyroxine and at the time of analysis all of the thyroid function tests were normal. GPx enzyme activity was measured by spectrophotometry at 340 nm. Serum selenium levels were measured by high-resolution continuum source graphite furnace atomic absorption. SePP, TPOAb (anti-thyroid peroxidase antibody), and TgAb (anti-thyroglobulin antibody) were determined by ELISA kits. T₄, T₃, T₃ uptake and TSH were also measured.Neither GPx activity nor SePP levels were significantly different in patients with Hashimoto’s thyroiditis or hypothyroidism compared to normal subjects. Although GPx and SePP were both lower in patients with hypothyroidism compared to those with Hashimoto’s thyroiditis and normal subjects but the difference was not significant. Serum Se levels also did not differ significantly in patients and normal subjects. We did not find any correlation between GPx or SePP with TPOAb or TgAb but SePP was significantly correlated with Se.Results show that in patients with Hashimoto’s thyroiditis or hypothyroidism who have been under treatment with levothyroxine and have normal thyroid function tests, the GPx, SePP and Se levels are not significantly different.