Euthyroid Adults Research Articles

A simplified method for diagnosis of gestational age in the newborn infant

concept that conversion of T4 to T~ depends upon a 5'monodeiodinase enzyme system that is immature at birth? The 3,3'T2 is thought to be derived at least in part from the peripheral conversion of T~ and reverse T~? In this infant, the 3,3'T~ level was high at birth, and remained elevated until the twenty-sixth day; therefore, it seems likely that the enzyme or enzymes capable of forming 3,3'T~ in thyrotoxicosis are operative at birth. LATS-P was present in high concentrations-i n the serum of both mother and infant, whereas LATS was measurable in both at low levels which could be considered nonspecific? The high concentration of LATS-P in the infant's serum when he was hyperthyroid and its reduction to undetectable levels when he became euthy-. roid suggest a role for this thyroid-stimulating immunoglobulin in the development of neonatal thyrotoxic0sis? Although the routine measurement, in all pregnant thyr0toxic women, of the thyroid-stimulating immunoglob.ulins LATS and LATS-P may be helpful in detecting neofmtal thyrotoxicosis, a definitive diagnosis of this disorder requires the demonstration of elevated iodothyronines in the infant. Although T4 and rT3 levels in cord serum are normally higher than in serum of euthyroid adults, ~ markedly elevated levels should suggest hyperthyroidism. An elevated cord serum T3 value may be diagnostic, since it is normally very low, ~. s and an elevated cord serum 3,3'T: level also indicates overproduction of iodothyronines. This patient illustrates that a variety of iodothyronines are abnormally elevated in neonatal thyrotoxicosis, and supports the concept that the disorder is produced by transplacental transmission of thyroid-stimulating immunoglobulins.

EVIDENCE FOR THYROIDAL SECRETION OF 3,3′,5′‐TRIIODOTHYRONINE IN MAN AND ITS CONTROL BY TSH

Thyroidal secretion of 3,3',5'-triiodothyronine (reverse T3, rT3) and its control by TSH was assessed by measuring (1) arterio-venous hormone gradients in patients undergoing surgery, (2) changes of hormone concentrations after induction of anaesthesia, and (3) changes induced by TRH administration. In ten patients in whom thyroid activity was under TSH control (parathyroidectomy and non-toxic goitre) increased thyroid vein/carotid artery ratios (TV/CA) for rT3 (mean TV/CA ratio 2.53) were found when compared to six patients with non-toxic goitre on suppressive doses of T4 (mean TV/CA ratio, 1.27) (P less than 0.05). The mean calculated operative secretion rate of rT3 was 12.5 microgram/day but only 2.4 microgram/day in patients receiving T4. In thirteen patients undergoing elective surgery induction of anaesthesia significantly increased rT3 levels. In nine euthyroid adults intravenous TRH (200 microgram) increased peripheral venous rT3 levels between 3 h (P less than 0.005) and 8 h (P less than 0.05) after the injection. It is concluded that significant amounts of rT3 are secreted by the thyroid gland at operation and this is, in part, under TSH control.

Measurements of 3,3′5′-Triiodothyronine (Reverse T3), 3,3′-L-Diiodothyronine, T3, and T4 in Human Amniotic Fluid and in Cord and Maternal Serum1 2

In order to assess fetal function at term, we have investigated parameters of thyroid hormone secretion and degradation in human amniotic fluid and in cord and maternal sera at delivery. The parameters measured included 3,3' L-diiodothyronine (3,3'T2), 3,3',5'-triiodothyronine (reverse T3), 3,3',5'-triiodothyronine (T3), thyroxine (T4), dialyzable T3 and T4, thyroxine binding globulin (TBG),and total iodine. The mean (+/- SE) 3,3'T2 concentrations in cord sera, amniotic fluid, and maternal sera were 20 +/- 1 ng/100 ml, 20 +/- 2 ng/100 ml,and 27 +/- 3 ng/100 ml, respectively. The normal range of this metabolite in the sera of non-pregnant adult subjects was 7 to 29 ng/100 ml. The mean (+/- SE) concentration of reverse T3 was higher in cord sera (315 +/- 16 ng/100 ml), amniotic fluid (82 +/- 25 ng/100 ml) and maternal sera (79 +/- 5 ng/100 ml) than in the sera of normal subjects (mean +/- 2 SD; 60 +/- 12 ng/100 ml). In amniotic fluid, T3, T4, and TBG were low, per cent dialyzable T3 and T4 were increased, and iodine concentrations were relatively normal in comparison to their respective serum levels in euthyroid adults. Since T3 and T4 were low in amniotic fluid our data indicate that measurements of 3,3'T2, reverse T3, or per cent dialyzable T3 and T4 in amniotic fluid would be the potentially most useful in establishing the diagnosis of congenital hypothyroidism before birth. In addition, these studies demonstrate that 3,3'T2 is normally present in the peripheral circulation and suggest that reverse T3 is the major source of 3,3'T2 in both amniotic fluid and cord blood.

THE RADIOIMMUNOASSAY OF 3,3‘,5’‐TRHODOTHYRONINE (REVERSE T3) IN UNEXTRACTED HUMAN SERUM

A specific, sensitive and simple double antibody radioimmunoassay for total serum 3,3',5'-triiodothyronine (reverse T3, rT3) in small volumes of unextracted human serum is described. High titre antisera were raised in rabbits using dl=rT3 or l-rT3 conjugated to bovine serum albumin. The selected antisera cross reacted less than 0-003% with triiodothyronine (T3) and 0-14% with thyroxine (T4). A stable high activity rT3 tracer was prepared by iodination of 3,3"-diiodo-l-thyronine by the chloramine-T method, and purified by column chromatography on Sephadex LH-20. Binding of rT3 to endogenous serum proteins was blocked by including 8-anilino-1-naphthalene sulphonic acid (ANS) in the assay. Mean rT3 levels in healthy euthyroid adults are 0-27 nmo1/1 (range 0-21-1-18); in cord sera 3-67 nmo1/1 (range 2-30-7-45) and in amniotic fluid taken during the second trimester 4-70 nmo1/1 (range 2-22-8-00). In approximately half the hypothyroid subjects, rTO levels were undetectable ( less than0-05 nmo1/1) and in the remaining subjects the mean rT3 level was 0-10 nmo1/1 (range 0-05-0-25).

Triiodothyronine and thyroxine in hyperthyroidism. Comparison of the acute changes during therapy with antithyroid agents.

In 66 untreated patients with hyperthyroidism, serum triiodothyronine (T(3)) and thyroxine (T(4)) concentrations were measured by immunoassay. The mean T(3) level was 478+/-28 ng/100 ml (all values mean+/-SEM) and the T(4) was 20.6+/-0.6 mug/100 ml. The serum T(4)/T(3) ratio by weight was 48+/-2 as opposed to a value of 71+/-3 in euthyroid adults. There was a significant inverse correlation of the T(4)/T(3) ratios with serum T(3) (r=0.77; P<0.01) but not with serum T(4)(r=0.21). These results suggested that relative overproduction of T(3) is consistently present in patients with hyperthyroidism. To examine the acute effects of various antithyroid agents on serum T(3) and T(4) concentrations, iodide, propylthiouracil (PTU), and methylmercaptoimidazole (MMI) were given alone to mine patients, and serial T(3) and T(4) measurements were made. There was an acute decrease in serum T(3) over the first 5 days in the three iodide and three PTU-treated patients which was greater than that seen in the MMI group. This suggested that PTU and MMI had different effects on T(3) production. To compare the effects of PTU and MMI under conditions in which thyroidal hormone release was minimized, these drugs were given in combination with iodide. The mean daily dosage of PTU was 827 (n=11) and of MMI was 88 (n=8). In the PTU+iodide group, the initial serum T(3) concentration was 586+/-61 ng/100 ml and decreased significantly to 326+/-41 on day 1 and to 248+/-21 on days 2 and 3, respectively, and did not change further on days 4 and 5. In the MMI + iodide group, basal serum T(3) was 645+/-90 ng/100 ml and decreased to 568+/-81, 452+/-73, and 344+/-51 on days 1, 2, and 3, respectively, and did not change thereafter. While the initial T(3) concentrations in serum were not different in the PTU and MMI groups, the T(3) concentrations in the PTU patients were significantly lower on days 1 and 2 and during the apparent plateau period on days 3-5. Serum T(4) concentrations decreased gradually in both groups, from 23.9+/-2.0 mug/100 ml, initially, to 17.5+/-1.6 on day 5 in the PTU group and from 22.0+/-2.6 to 14.6+/-2.0 in the MMI-treated patients. The T(4) values were not significantly different at any time. These changes resulted in increases in the serum T(4)/T(3) ratios in both groups, but these ratios were substantially higher in the patients treated with PTU + iodide. The initial serum T(4)/T(3) ratio was 43+/-3 and increased to 74+/-7 and 88+/-7 on days 1 and 2 in the PTU group, reaching a plateau value of 91+/-7 during days 3-5. Comparable values for MMI-treated patients were 35+/-2, 42+/-3, 52+/-6, and 54+/-3 during the plateau period. Previous investigations have shown that PTU inhibits T(4) deiodination in hyperthyroid patients and decreases T(3) production from T(4) in animals. The greater acute decrease in serum T(3) and the higher serum T(4)/T(3) ratios in the PTU-treated patients seems best explained by an inhibition of peripheral T(3) production by this agent. This conclusion is further supported by a direct relationship between the T(4)/T(3) ratio on days 3-5 and the dose of PTU administered. These results further suggest that both thyroidal and extrathyroidal pathways contribute substantially to the apparent overproduction of T(3) in hyperthyroidism.

Plasma thyrotrophin levels during pregnancy.

SummaryPlasma levels of thyrotrophin (TSH) were studied by radio‐immunoassay using homologous human TSH in 142 normal pregnant women and in 19 women with pre‐eclampsia, in 2 normal pregnant women who were followed up for almost a month, in 1 patient with a hydatidiform mole before and after hysterotomy, in 10 women 30 minutes after delivery and in the arterial and venous cord blood of 11 newborn infants. Thirty‐one normal euthyroid adults and 23 normal children were studied as controls.An increase in TSH plasma levels was found from the 7th week of pregnancy until delivery. Thirty minutes after delivery, and in the molar pregnancy 15 minutes after hysterotomy, the TSH levels returned to the upper normal range. In pre‐eclampsia the TSH plasma levels were found to be higher than in normal pregnancy. In the newborn at delivery the hypophyseal thyrotrophic function appeared to be slightly higher than in normal children. The increased plasma TSH level during pregnancy is probably due to the placental thyrotrophic‐like peptide secretion.During the different stages of purification from the placenta of human chorionic somatomammotrophin, immunoreacting thyrotrophic factor was found only in the starting material.The existence of a cross‐reaction between human TSH and human chorionic thyrotrophin was confirmed.

Determination of erythrocyte carbonic anhydrase B and C: an aid in the diagnosis of thyroid disorders?

AbstractTwo genetically distinct forms of erythrocyte carbonic anhydrase, form B and form C, have been assayed by means of electrophoresis on cellulose acetate membranes in 92 euthyroid adults and in 49 patients suffering from thyroid disorders. A negative correlation was found between the concentration of erythrocyte carbonic anhydrase form B and plasma thyroxine. This finding is shown to be due to an effect of the thyroid hormone system on the synthesis of isoenzyme B in the red blood cell precursors. The use of the carbonic anhydrase B assay as a means of measuring the action of the thyroid hormone on the body cells is discussed.

The sensitive and precise measurement of serum thyroxine by saturation analysis (Competitive protein binding assay)

Summary 1. A saturation assay for serum thyroxine is described with particular reference to the attainment of highest assay sensitivity and precision. The technique provides an illustration of the application of theoretical precepts put forward by Ekins, Newman and O'Riordan relating to the choice of optimum reagent concentrations in all saturation assay systems, including radioimmunoassays, competitive protein binding assays and, with slight modification, radioenzymic assays. 2. Ion exchange resin and charcoal techniques for the sequestration of free from bound moieties are described and the sensitivities attained with each system compared. Highest sensitivity to date has been achieved with the resin method ; under normal routine conditions the minimum detectable concentration of thyroxine in assay incubation mixtures is about 70 pg/ml, corresponding to roughly 0.5 ng/ml serum. 3. The use of the assay in clinical diagnosis is exemplified by the presentation of normal ranges for euthyroid adults, for pregnant women and women on oral contraceptives, and by the measurement of the response to exogenous thyroidstimulating hormone and tri-iodothyronine.

Free Thyroxine in Serum in Relation to Thyroid Function

The concentration of free thyroxine (FT 4 ) in serum, measured by a direct method, was 1.77 ± 0.25 mμg/100 ml (mean ± SD) in normal euthyroid adults, 8.47 ± 2.87 in hyperthyroid patients, and 0.54 ± 0.29 in hypothyroid patients. Pregnant euthyroid patients and normal women taking estrogens had increased values for proteinbound iodine (PBI) in serum, while values for the resin uptake of liothyronine I 131 (RT 3 ) were decreased; but free thyroxine values were normal or slightly decreased. Euthyroid patients with various chronic diseases had decreased PBI values in association with increased RT 3 values, but free thyroxine values were normal. Acutely or severely ill euthyroid patients had increased free thyroxine values that often exceeded the normal range. The correlation between values for free thyroxine and the PBI•RT 3 product was good in all groups except the sick euthyroid patients. The PBI•RT 3 product closely reflected the state of thyroid function in all of the groups of patients.

Indices during administration of T 4 and T 3 to euthyroid adults

In short-term studies in euthyroid subjects, serum PBI remained constant during the daily ingestion of 3 grains of desiccated thyroid, Proloid, or thyroglobolin, increased as expected with 300 μg. of L-thyroxine (T 4), and decreased as usual with 100 μg. of L-triiodothyronine (T 3). Therapy with mixtures of T 4 and T 3 in a 5:1 and 4:1 ratio (185:37.5 μg. and 180:45 μg.) was associated with sporadic increases in serum PBI above 8 μg. per cent, though mean values for the treatment group were in the euthyroid range. Such sporadic rises in serum PBI did not occur with a 3:1 mixture (150:50) but occasional decreases were recorded. The serum PBI regularly decreased during treatment with a 1:1 mixture (75:75 μg). So-called equivalent replacement dosages of certain thyroid hormone preparations administered for several weeks to euthyroid individuals may be associated with decreases in the serum cholesterol and, less often, in the triglycerides and in shortening of certain indices of the ankle reflex time. In our trials, these effects were most consistently observed during ingestion of T 3 alone or of desiccated thyroid but were present sporadically during trials with the other thyroid hormone mixtures.

PLACENTAL TRANSPORT OF THYROXINE.

Measurements of BEI, triiodothyronine 131I resin uptake (T3U) and thyroxine 131I resin uptake (T4U) were conducted in 15 women with uncomplicated pregnancies and in their infants at the time of delivery and values were compared with those of euthyroid adults. In 13 additional women at term (with uncomplicated pregnancies) given intravenous loads of 500–8000 μg sodium Lthyroxine, BEI and T3U were measured before and 1 hr postloading and in maternal and cord blood specimens at delivery. In control maternal subjects mean BEI was significantly higher than in the newborn or in euthyroid adults. Newborn and euthyroid adult values did not differ significantly. Mean T3U and T4U in these subjects increased progressively from maternal to newborn to euthyroid adult groups. These data suggest that the normal gradient of placental thyroxine transport is fetal-maternal. After maternal thyroxine loading, newborn BEI and T3U increased progressively with increasing maternal thyroxine load and increasing diffusion time, but these increases were much less than in maternal sera even after 8000 μg thyroxine loads and relatively prolonged diffusion time. It is concluded that maternal-fetal placental transport of thyroxine in human term gestation is limited by the increased concentrations of maternal thyroxine-binding protein as well as by an inherent placental impermeability to thyroxine.

Thyroid function studies in children: normal values for thyroidal I 131 uptake and PBI 131 levels up to the age of 18.

RADIOIODINE has been used in normal children to study thyroid function. All but one of the previous studies concerning children have been limited, in that only the concentrating ability of the thyroid for iodine has been tested. This function was measured as the percentage thyroidal uptake of the administered dose at twenty-four hours (1–6) or at forty-eight hours (7). In one study (8), the secretion rate of proteinbound radioiodine (PBI131) of serum was measured at various intervals after I131 administration, but there was no information about the age groups tested. This study was undertaken to establish normal standards for thyroidal uptake and serum PBI131 values at various ages and to clarify the discrepancies in normal uptake values reported from various parts of the United States. The data presented indicate that the thyroid gland in children up to the age of 4 years, and possibly later, is normally in a state of “hyperactivity” when compared to that of the euthyroid adult.

Protein-bound iodine levels in normal and in diabetic children.

THE DEVELOPMENT of reliable semimicroanalytic procedures has permitted more precise studies of the circulating iodine fractions.¹As a consequence, much of the confusion resulting from methodologic inadequacies and from the use of blood instead of serum samples has been eliminated. In brief, applications of these methods have revealed that the level of serum inorganic iodide in healthy adults varies, as might be expected, with the intake of this halide, but with an ordinary diet it only infrequently exceeds 1 γ per 100 ml.²The major fraction, called protein-bound or serum-precipitable iodine, ranges in euthyroid adults between 4 and 8 γ per 100 ml.,³remains quite constant in any one person from week to week.⁴and from the point of view of solubility, behaves like thyroxine.⁵Thyrotoxicosis⁶and uncomplicated pregnancy⁷are characterized by elevations of both protein-bound iodine and of thyroxine.⁸Hypothyroidism, or

ALTERATIONS IN SERUM IODINE FRACTIONS INDUCED BY THE ADMINISTRATION OF INORGANIC IODIDEL IN MASSIVE DOSAGE*†

IT HAS been shown that in euthyroid adults on an intake of inorganic iodide limited to that ordinarily present in the diet the serum precipitable or protein-bound iodine remains relatively constant within the range of 4.0 to 8.0 gamma per cent (1, 2). Under these circumstances the inorganic iodide in serum also remains constant at approximately one gamma per cent (3, 4). If, however, the intake of inorganic iodide is greatly increased, the concentration of this inorganic fraction rises several hundred fold, or more (4, 5). The present study defines alterations in serum proteinbound or precipitable iodine which accompany such rises during the administration of inorganic iodide in massive doses. Materials and Methods The pertinent clinical data on 8 patients who received up to 3 grams of potassium iodide or up to 7 ml. of a saturated solution of the same salt daily during periods as long as six months are presented in the legends to Figures 2 through 9. The sera of these subjects were analyzed at intervals ...