Replacement Doses Of Thyroxine Research Articles

The clinical significance of low dose biotin supplements (

BackgroundIn the last decade, the combination of the widespread use of streptavidin–biotin technology and biotin–containing supplements (BCS) in the daily clinical practice, have led to numerous reports of erroneous hormone immunoassay results. However, there are no studies assessing the clinical and biochemical significance of that phenomenon, when treating patients with hypothyroidism. Therefore, a prospective study was designed to investigate the potential alterations in the measurement of thyroid hormone concentrations and clinical consequences in patients with hypothyroidism using low -dose BCS containing less than 300 μg/day.MethodsFifty-seven patients on thyroxine supplementation, as a result of hypothyroidism and concurrent use of BCS at a dose <300μg/day for 10 to 60 days were prospectively evaluated. Namely, TSH and free T4 (FT4) concentration measurements were performed, during BC supplementation and 10 days post BCS discontinuation and compared to 31 age-matched patients with supplemented hypothyroidism and without BCS.ResultsA statistically significant increase in TSH and decline in FT4 concentrations was observed after BCS discontinuation. However, on clinical grounds, these modifications were minor and led to medication dose adjustment in only 2/57 patients (3.51%) in whom TSH was notably decreased after supplement discontinuation.ConclusionOur study suggests that changes in thyroid hormones profiling, due to supplements containing low dose biotin, are of minimal clinical relevance and in most cases don’t occult the need to adjust the thyroxine replacement dose in patients with hypothyroidism. Larger, well-designed trials are required to further evaluate this phenomenon.

Basal Serum Thyroxine Level should Guide Initial Thyroxine Replacement Dose in Neonates with Congenital Hypothyroidism

Objective:Initial high-dose sodium levothyroxine (Na-LT4) (10-15 μg/kg/day) replacement for primary congenital hypothyroidism (CH) is recommended in guidelines. However, high-dose Na-LT4 risks iatrogenic hyperthyroidism. The aim of this study was to investigate the normalizing effect of varying initial doses of Na-LT4 on serum thyroid hormone levels.Methods:Fifty-two patients were analyzed retrospectively. The patients were classified into mild (27/51.9%), moderate (11/21.1%) and severe (14/26.9%) CH, based on initial free thyroxine (fT4) levels. Time taken to achieve target hormone levels was compared within groups.Results:Initial mean Na-LT4 doses for mild, moderate and severe disease were 6.9±3.3, 9.4±2.2 and 10.2±2 μg/kg/day. Serum fT4 levels reached the upper half of normal range (>1.32 ng/dL) in a median of 16, 13 and 16 days in patients with mild, moderate and severe CH with the mean time from initial treatment to first control visit of 14.8±6 days (range 1-36). There was no significant difference in terms of time to achieve target fT4 hormone levels according to disease severity (p=0.478). Seven (25.9%), eight (72.7%) and eight (57.1%) patients experienced hyperthyroxinemia (serum fT4 >1.94 ng/dL) in the mild, moderate, and severe CH groups at the first visit, respectively (p=0.016).Conclusion:Not all patients diagnosed with CH require high-dose Na-LT4. Initial dose of Na-LT4 may be selected on the basis of pretreatment thyroid hormone levels. Some patients with moderate and severe CH, experienced iatrogenic hyperthyroxinemia even though the dose was close to the lower limit of the recommended range in guidelines. We suggest that lower initial doses may be appropriate with closer follow-up within the first week.

Low replacement doses of thyroxine during food restriction restores type 1 deiodinase activity in rats and promotes body protein loss

During food restriction, decreased basal metabolic rate secondary to reduced serum thyroid hormones levels contributes to weight loss resistance. Thyroxine (T(4)) and 3,3',5-tri-iodothyronine (T(3)) administration during caloric restriction produce deleterious side effects; however, the administration of physiological doses of T(4) during food restriction has never been evaluated. The aim of this study was to analyze the effects of low replacement doses of T(4) in Wistar rats subjected to 40% food restriction. Food restriction for 30 days led to significantly reduced liver type 1 deiodinase activity, serum TSH, leptin, T(4), T(3), metabolic rate, and body mass. The significant reduction in hepatic deiodinase activity found during food restriction was normalized in a dose-dependent manner by T(4) replacement, showing that decreased type 1 deiodinase (D1) activity is secondary to decreased serum thyroid hormone levels during caloric restriction. The lowest replacement dose of T(4) did not normalize resting metabolic rate, but was able to potentiate the effects of food restriction on carcass fat loss and did not spare body protein. The highest dose of T(4) produced a normalization of daily oxygen consumption and determined a significant reduction in both carcass fat and protein content. Our results show that serum T(4) normalization during food restriction restores serum T(3) and liver D1 activity, while body protein is not spared. Thus, decreased serum T(4) during caloric restriction corresponds to a protective mechanism to avoid body protein loss, highlighting the importance of other strategies to reduce body mass without lean mass loss.

Post-thyroidectomy thyroxine replacement dose in patients with or without compensated heart failure: The role of cytokines

Objective: To investigate the potential association between serum inflammatory cytokine levels and post-thyroidectomy thyroxine replacement dose in patients with or without compensated heart failure. Patients and methods: The study included 42 patients (group A: 20 men, mean age of 54.5 ± 6.8 years) with NYHA I or II heart failure and 54 patients (group B: 25 men, mean age of 52.9 ± 7.1 years) without heart failure. All patients had undergone total thyroidectomy and were euthyroid on a stable thyroxine replacement dose. Serum Interleukin-1b (IL-1b), Tumor Necrosis Factor α (TNF-α), Interleukin-6 (IL-6), TSH, T 3, T 4, fT 3 and fT 4 were measured. Results: Both groups exhibited a significant positive correlation between IL-6 and levothyroxine replacement dosage (group A: r = 0.708, p < 0.001; group B: r = 0.345, p = 0.012) and a negative correlation between IL-6 and T 3 (group A: r = −0.342, p = 0.023, group B: r = −0.294, p = 0.035). Significant independent predictors of levothyroxine replacement dosage were IL-6 ( p < 0.001) and TNF-α ( p = 0.007) in group A (58.3% of dosage variation) and only IL-6 ( p = 0.012) in group B (10.1% of dosage variation). Conclusions: In both groups, a significant positive correlation was observed between IL-6 and levothyroxine replacement dosage, but this correlation was stronger in group A. In the same group, there was evidence for a more pronounced influence of cytokines on levothyroxine dosage.

Thyroxine replacement dose in patients with Hashimoto disease: A potential role for interleukin-6

Objective: To investigate the potential association between serum inflammatory cytokine levels and thyroxine replacement dose in patients with Hashimoto disease. Patients and methods: The study included 40 patients (12 men) with a mean age of 56.52 ± 6.12 years who had hypothyroidism due to Hashimoto disease. Serum interleukin-1b (IL-1b), tumour necrosis factor α (TNF-α) and interleukin-6 (IL-6) levels, as well as TSH, T 3 and T 4 were measured (ELISA). Results: Serum IL-6 showed a significant positive correlation both with total thyroxine replacement dose ( r = 0.551, p = 0.001) and with dose per kilogram of body weight ( r = 0.482, p = 0.002). There was also a significant negative linear correlation between serum IL6 and T 3 ( r = −0.322, p = 0.043), as well as between serum IL6 and T 3/T 4 ratio ( r = −0.332, p = 0.036). A further significant ( r = 0.419, p = 0.007) positive association was demonstrated between IL6 and TNF-α. However, no association was found between T 3 or T 3/T 4 ratio and TNF-α or IL1b. Conclusions: In patients with Hashimoto disease serum IL-6 levels are positively associated with thyroxine replacement dose and negatively associated with T 3 and T 3/T 4 ratio. These results are possibly attributable to the inhibitory effect of IL6 on deiodination of T 3 and imply a role for IL6 in determining thyroxine replacement dose among these patients.

Congenital Hypothyroidism (Cretinism) in neuroD2-Deficient Mice

Mice lacking neuroD2, a basic helix-loop-helix transcription factor involved in brain development, show growth retardation and other abnormalities consistent with hypothalamic-pituitary-thyroid (HPT) axis dysfunction. neuroD2 is expressed in the paraventricular hypothalamic nuclei, the anterior lobe of pituitary, and the thyroid gland. In neuroD2-deficient mice, thyrotropin-releasing hormone, thyroid-stimulating hormone, and thyroid hormone are decreased in these three regions, respectively. neuroD2-null mice typically die 2 to 3 weeks after birth, but those treated with replacement doses of thyroxine survived more than 8 weeks. These data indicate that neuroD2 is expressed throughout the HPT axis and that all levels of the axis are functionally affected by its absence in mice.

The effect of l-thyroxine on the anaemia response in Trypanosoma congolense infected rabbits

The development of anaemia is a major pathological manifestation in chronic trypanosomosis. The anaemia in African trypanosomosis coincides with a marked decrease in plasma concentration of both thyroxine (T 4) and 3,5,3′ triidothyronine (T 3). To evaluate the effect of trypanosome-induced hypothyroidism on the development of anaemia, sexually mature white New Zealand rabbits were used. Three groups were set up, each of ten rabbits: one group was infected with Trypanosoma congolense; the second group was infected but given replacement doses of thyroxine (treated); the third group was not infected. Small volumes of blood were collected for the determination of parasitaemia and packed cell volume (PCV). The concentrations of T 3 and T 4 were measured in plasma by radioimmunoassay. The decrease in PCV correlated closely ( y= −0.38 x + 15.2; r=0.82, P=0.001) with the intensity and duration of parasitaemia. The critical PCV value was 0.15 11 −1 with a peak parasitaemia of approximately 5×10 6 trypanosomes ml −1 of blood. There was a significant correlation between the plasma T 3 and PCV ( y=0.049 x+0.57; r=0.66, P=0.020). There was also a good positive correlation between T 4 and PCV ( y=14.5+3.03; r=0.95, P<0.001) in the infected untreated group. The PCV levels were significantly different among the three groups of animals ( P<0.05). The infected-treated animals sustained longer periods of infection than the infected and untreated ones. The sustained physiological level of bioactive thyroid hormones T 3 and T 4 significantly arrested the decline in PCV as the disease progressed. The hormonal treatment thus enhanced the survival of the animals infected with Trypanosoma congolense.

Thyroxine replacement in post‐radioiodine hypothyroidism

Thyroxine replacement dose in 70 patients with post-radioiodine (for Graves' thyrotoxicosis) hypothyroidism was compared with that in 34 patients with autoimmune hypothyroidism matched for age and sex and diagnosed during the same period. Median replacement dose in the post-radioiodine group (100 micrograms daily) was significantly lower (P = 0.006) than in the autoimmune hypothyroid group (137.5 micrograms daily). Furthermore there was marked variation in the time elapsing from onset of post-radioiodine hypothyroidism to achievement of a given maintenance dose. These findings may be explained by persistence of non-TSH mediated thyroid function, after radioiodine therapy for Graves' thyrotoxicosis. The observations indicate the potential risk of overtreatment with thyroxine in post-radioiodine hypothyroidism unless the dose is carefully titrated against serum TSH levels. Final thyroxine requirements may not be evident in the initial phase of treatment and patients with apparently low maintenance thyroxine requirements require long-term follow up.

Erythrocyte Carbonic Anhydrase I Concentration in Patients Receiving Thyroxine.

We recently reported that the red blood cell (RBC) carbonic anhydrase I (CAI) concentration in patients with hyperthyroidism is reduced and reflects the patient's mean thyroid hormone level over the preceding months. In this study, RBC CAI concentrations were measured in patients with thyroid nodules who were receiving suppressive doses of thyroxine (group I) and compared with those obtained in patients with primary hypothyroidism receiving replacement doses of thyroxine (group 2). Of the 17 patients in group 1, 16 (94%) had elevated plasma free T4 levels, but all 17 had normal free T3 levels. Of the 17 patients in group 2, 16 (94%) had normal free T4 levels and all 17 had normal free T3 levels. Plasma TSH concentrations in group 1 were all below the lower limit of sensitivity of 0.04 mU/l. In group 2, 11 had normal and 6 had slightly elevated plasma TSH concentrations. The mean (+/- SD) RBC CAI concentration in group 1 (300 +/- 53 nmol/g Hb) was significantly lower than that in group 2 (340 +/- 57 nmol/g Hb). The RBC CAI concentration was significantly correlated with both the concentration of plasma free T4 and free T3. These observations indicate that in patients receiving suppressive doses of thyroxine a slight increase in the plasma free T4 concentration produces a slight but significant decrease in RBC CAI levels.

Cold exposure rapidly induces virtual saturation of brown adipose tissue nuclear T3 receptors.

Cold exposure induces a rapid increase in uncoupling protein (UCP) concentration in the brown adipose tissue (BAT) of euthyroid, but not hypothyroid, rats. To normalize this response with exogenous 3,5,3'-triiodothyronine (T3), it is necessary to cause systemic hyperthyroidism. In contrast, the same result can be obtained with just replacement doses of thyroxine (T4) and, in euthyroid rats, the normal response of UCP to cold occurs without hyperthyroid plasma T3 levels. Consequently, we explored the possibility that the cold-induced activation of the type II 5'-deiodinase resulted in high levels of nuclear T3 receptor occupancy in euthyroid rats. Studies were performed with pulse injections of tracer T3 or T4 in rats exposed to 4 degrees C for different lengths of time (1 h-3 wk). Within 4 h of cold exposure, we observed a significant increase in the nuclear [125I]T3 derived from the tracer [125I]T4 injections (T3[T4]) and a significant reduction in the nuclear [125I]T3 derived from [125I]T3 injections (T3[T3]). The number of BAT nuclear T3 receptors did not increase for up to 3 wk of observation at 4 degrees C. The mass of nuclear-bound T3 was calculated from the nuclear tracer [125I]T3[T3] and [125I]T3[T4] at equilibrium and the specific activity of serum T3 and T4, respectively. By 4 h after the initiation of the cold exposure, the receptors were greater than 95% occupied and remained so for the 3 weeks of observation. This effect of cold was hindered by prazosin, a drug that prevents the cold-induced activation of 5'-deiodinase. We conclude that the simultaneous activation of the deiodinase with adrenergic BAT stimulation serves the purpose of nearly saturating the nuclear T3 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Variations in Serum Thyroxine Concentrations with Time after an Oral Replacement Dose

Serum thyroxine concentrations were measured sequentially in eight healthy male volunteers after the oral administration of one of two brand name, commercially available thyroxine tablets. In all cases, levels peaked at 2 hours and did not return to baseline values until 24 hours after dosing. From 2 through 10 hours, statistically significant elevations in serum thyroxine concentrations were observed. Such fluctuations may be important in evaluating laboratory results in patients receiving replacement doses of thyroxine.

Thyrotropin "receptors" in normal and neoplastic human thyroid tissue.

lf a maximum binding occurred within 15 minutes at 4” and 37”C, pH 7.45, and remained stable for 5 hours. (3) Optimum binding occurred at pH 6.0. (4) Binding of tracer quantities of ““I-bTSH increased in a nearly linear fashion with increasing particulate protein concentrations up to 33 t.tg/ml. (5) Both a high and low aj%ity binding site were usually present in NT, A, and PC. (6) The maximal percentage of binding of tracer quantities of “‘I-bTSH (mean + SE) varied from experiment to experiment in both the normal and neoplastic thyroid tissue. Because of this variation, binding to neoplastic normal thyroid tissue always was compared with binding to adjacent histologically normal thyroid tissue removed from the same patient. The maximum percentage of binding of tracer quantities of “‘I-bTSH (mean + SE) in the particulate fraction (33 pg of protein/ml) in NT (15.7 + 2. I) was greater (P < 0.001) than in A (5.4 + 0.7). The maximum percentage of binding, although lower in NTfrom patients with thyroid cancer than in patients with thyroid adenomas, was comparable in NT (8.0 + 1.2), in PC (8.8 +- 1.8), and in MC (6.2 + 0.4). (7) The apparent a@& constants (Ka, and Ka,) for A and PC were similar to the apparent afini~ constants obtained with NT (8) Th e number of high afinity binding sites in the particulate fraction was greater (P < 0.025) in NT (4.72 ? 0.89 X IO”) than in A (0.55 z? 0.37 X 1O’l) but was comparable in NT and PC. Therefore, normal and neoplastic thyroid tissue appears to have specific TSH binding sites. This helps to explain why some tumors regress in patients given exogenous thyroid hormone and lends support to the notion that all patients with d$erentiated thyroid tumors should receive full replacement doses of thyroxine after thyroidectomy.

871 BONE DYNAMICS AND MINERAL METABOLISM IN A PATIENT WITH TURNER SYNDROME AND A CRANIOPHARYNGIOMA TREATED WITH GROWTH HORMONE

Trephine biopsy of tetracycline labeled bone, parathyroid hormone levels and bone densitometry using photon absorptiometry were accomplished in a 14-year-old girl with 45,X karyotype who also has a craniopharyngioma. At the time of the initial studies, she was taking replacement hydrocortisone, 10mg. every morning and 5mg. at night and 150mcg. of Thyroxine daily. The cell and tissue level dynamics of bone remodelling were elevated and slightly above normal compatible with high turnover bone. In retrospect this may have been related to the slightly high thyroxine replacement dose. Following eight months of growth hormone treatment, the dynamics showed further increase in bone activity at both the haversian and endosteal-cortical surfaces. The thyroxine replacement remained constant. She grew three inches, whereas she had previously only grown ½ inch per year. The parathyroid hormone levels did not change significantly. The bone densitometry was 7 standard deviations below normal for age and sex and did not change significantly with treatment.

EFFECT OF PROLONGED ORAL ADMINISTRATION OF TRH ON PLASMA LEVELS OF THYROTROPHIN AND PROLACTIN IN NORMAL INDIVIDUALS AND IN PATIENTS WITH PRIMARY HYPOTHYROIDISM

Forty mg TRH/day was given orally for 3 weeks to 10 euthyroid women and 10 women with primary hypothyroidism on low replacement doses of thyroxine. Once weekly oral TRH was replaced by an iv TRH-test (0.4 mg) with measurement of serum concentration of TSH, prolactin (PRL), thyroxine (T4), triiodothyronine (T3) and cholesterol. In the normal group, mean serum T4 concentration increased after one week and remained elevated. Serum TSH concentration showed a slight tendency to decline. Maximal rise in TSH concentration after iv TRH (deltaTSH) fell from a mean of 4.0 ng/ml to 1.4 ng/ml within one week and stayed low. T3, cholesterol, PRL and deltaprl were normal and unchanged throughout. In the hypothyroid group T4, T3, cholesterol, PRL and deltaPRL were not influenced by the TRH administration. In 2 patients (with the highest serum T4 concentrations) serum TSH concentration was normal and resistant to iv TRH. Of the 8 patients with elevated TSH, basal level and deltaTSH did not change in 2 (with subnormal T4 levels and the highest TSH levels). In the other 6 (with intermediate T4 levels) basal TSH fell from a mean of 10.1 ng/ml to 4.2 ng/ml, and deltaTSH from 10.0 ng/ml to 3.3 ng/ml after three weeks. It is concluded that in addition to feed-back effect of thyroid hormones, the pituitary response to long-term administration of TRH is determined by other factors. Among these may be reduced pituitary TRH receptor capacity and the activity of the TSH producing cells.

Effect of hypophysectomy on protein synthetic-activity of free and bound hepatic ribosomes from insulin-deficient rats

Acute insulin deficiency in rats results in a decrease in the in vitro protein synthetic activity of isolated hepatic membrane-bound ribosomes and an increase in activity of free ribosomes. These changes are prevented by concomitant insulin treatment and are reversed by the administration of insulin. The current study evaluated the role of the pituitary in the genesis of these changes. The severity of diabetes produced by streptozotocin was less in hypophysectomized (Hx) rats, and in Hx rats receiving hormone replacement, as compared with similarly streptozotocin-treated intact rats. Although acute insulin deficiency in intact rats produced the previously described increase in protein synthetic activity of free hepatic ribosomes and decrease in activity of hepatic bound ribosomes, these changes did not occur in Hx rats, even when Hx rats received replacement doses of thyroxine, ACTH, and growth hormone. Thus, the changes in hepatic protein synthetic activity that occur in rats with acute experimental diabetes mellitus are secondary to the metabolic sequalae of insulin lack and the response of the pituitary gland to insulin deficiency.

Identification of the effects of thyroxine mediated by the hypophysis.

ACCORDING to the concepts of Classical Endocrinology, an effect of thyroxine may be defined as the restoration by this hormone1 of a physiological process altered by thyroidectomy. Such effects are not necessarily due to a direct action of thyroxine on an end organ; some may result from complex hormonal interactions. Thus, Evans and his associates have suggested that the growth-promoting effect of thyroxine is exerted through the hypophysis (Scow et al., 1949; Koneff et al., 1949; and Becks et al., 1950). It was decided to examine systematically the relationship between the hypophysis and the production of the effects of thyroxine. To this end, hypophysectomized animals were treated with replacement doses of thyroxine and the results obtained were compared with those observed in thyroidectomized animals similarly treated. The conclusions derived from this comparison helped to clarify the role played by the hypophysis in the production of thyroxine effects.