The appropriate use of diagnostic services: (III). Thyroid disease and the laboratory.
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Aged↗
Biomedical subjects
R L Himsworth
Publications and source records attributed to R L Himsworth.
Exposure of thyroxine residues in human thyroglobulin. Two-site binding studies.
Human thyroglobulin (Tg) could be adsorbed through one of its thyroxine (T4) residues by either of two T4-binding antibodies which had been covalently attached to Sepharose- CL4B . The antibodies used were (i) a purified human autoantibody specific for a T4-containing epitope in human Tg, or (ii) a rabbit antibody raised against T4 conjugated to bovine albumin side chains. Tg adsorbed by either immobilized antibody could then itself adsorb either type of antibody free in solution on to a further T4 residue. At least two T4 residues in human Tg are therefore sufficiently exposed to interact with T4-binding antibodies. Furthermore, these T4 residues are sufficiently far apart to allow the binding of two immunoglobulin molecules simultaneously. Previous observations of a marked preference by human autoantibodies for one of the T4-containing epitopes in Tg therefore reflect a higher binding energy with that epitope rather than an inability to interact with others. The T4-containing epitope which preferentially reacts with human Tg autoantibodies must therefore have a distinctive topography.
Adsorption↗
Total and free thyroid hormone concentrations in patients receiving maintenance replacement treatment with thyroxine.
Total and free serum concentrations of thyroxine and triiodothyronine were measured in 122 subjects with hypothyroidism who were clinically well while receiving conventional replacement treatment with thyroxine. In a third of patients concentrations of total and free thyroxine were raised, often considerably; nevertheless concentrations of total and free triiodothyronine were usually normal. Though significant correlations were obtained between total triiodothyronine concentrations and total thyroxine concentrations (p less than 0.001) and between the triiodothyronine concentrations and free thyroxine concentrations (p less than 0.001) the slope of the line of the regression equation describing these correlations was small, hence large increases in both total and free thyroxine concentrations were accompanied by only modest increases in total and free triiodothyronine concentrations. The presence of total or free thyroxine concentrations above normal in patients taking thyroxine therefore are not necessarily of clinical consequence. In the assessment of adequacy of replacement treatment with thyroxine the most logical combination of in vitro thyroid function test results may be a normal thyrotrophin concentration and normal free triiodothyronine concentration.
Adult↗
Subfractionation of human immunoglobulin G with dye-Sepharose adsorbents.
Seventeen reactive dyes were separately covalently attached to Sepharose-4B and examined for their ability to subfractionate the immunoglobulin G found in human serum. Each dye-Sepharose-4B adsorbent appeared to bind a characteristic proportion of the protein when tested with "pure" preparations. It is suggested that this is due to stereospecific interactions between each dye and various interaction sites on the immunoglobulin G molecules. These sites of interaction are not those which define the four major subclasses of the H-chain nor those which distinguish the kappa and lambda light chains. The adsorption may be influenced by the presence of other proteins when serum samples are tested due to competition for binding to the immobilised ligands but sequential use of the adsorbents can progressively enrich a particular immunological activity in human serum. This method offers a convenient and gentle way to subfractionate immunoglobulin G especially when the antigen is not known or unavailable for conventional affinity chromatography.
Adsorption↗
A prealbumin variant with an increased affinity for T4 and reverse-T3.
A euthyroid adult female (LC) was found to have persistently raised concentrations of total T4 (159 nmol/l) and rT3 (500 pmol/l) in her serum in association with a normal T3 (2.1 nmol/l). Serum concentrations of all three T4-binding proteins were within normal limits. A variant prealbumin with an increased affinity for T4 was found to be responsible for the raised serum level of T4. Unlike normal prealbumin, the variant also bound appreciable amounts of rT3. The affinity constant for T4 binding to prealbumin LC was 5.5 X 10(8) l/mole which is sevenfold higher than that obtained for normal prealbumin (8.5 X 10(7) l/mole). The affinity constant for the binding of rT3 to prealbumin LC was 2.0 X 10(6) l/mole while that for the normal protein was unmeasurable by our method. The T4-binding capacity of prealbumin LC in serum was within the normal range indicating that there is no new additional T4-binding site on the protein. Prealbumin LC has the same molecular size as the normal protein, hence it is likely that the tetrameric structure has been preserved. The electrophoretic mobility of prealbumin LC was normal indicating no alteration in charge. It is postulated that the increased affinity for T4 (and presumably for rT3) results from a hydrophobic amino-acid substitution in the prealbumin monomer.
Adult↗
Binding of amiodarone by serum proteins and the effects of drugs, hormones and other interacting ligands.
Amiodarone is chiefly bound to albumin (62.1%) and much of the remainder (33.5%) is carried on a high molecular weight protein, probably beta-lipoprotein. Analysis of data for amiodarone binding to albumin revealed a high affinity primary binding site (Ka 5.6 X 10(6) litre mol-1) with about four secondary sites (average Ka 1.9 X 10(5) litre mol-1). Studies of the binding of amiodarone in serum revealed one type of binding site only with an affinity constant (Ka 4.2 X 10(6) litre mol-1) similar to that of the primary site on albumin. The secondary albumin binding sites do not seem therefore to be utilized in whole serum and the affinity of the lipoprotein must be similar to that of the primary amiodarone binding site on albumin. The effects of a wide range of compounds on albumin binding of amiodarone were examined by equilibrium dialysis. Quinidine, amitriptyline, cephazolin and palmitate decreased albumin-bound [125I]amiodarone. Neither warfarin nor digoxin affected the binding of amiodarone by albumin, thus of the three drugs known to be potentiated by concomitant amiodarone administration, only potentiation of quinidine could be explained by displacement from serum albumin. Rifampicin, frusemide, phenytoin, (-)-adrenaline, bromocresol green, (-)-noradrenaline and bromocresol purple were found to increase binding of [125I]amiodarone by albumin.(ABSTRACT TRUNCATED AT 250 WORDS)
Amiodarone↗
Total serum thyroxine and triiodothyronine; a comparison between Graves' disease and hyperthyroxinaemia due to thyroxine replacement.
Serum concentrations of total thyroxine (T4) and total triiodothyronine (T3) were measured in a group of patients (n = 113) presenting with untreated hyperthyroidism due to Graves' disease and in subjects receiving oral T4 replacement (n = 93) in whom the total T4 concentration was supraphysiological (greater than 150 nmol/l). The mean total T4 concentration in the hyperthyroid group was 226 nmol/l, SD 59, range 151-420, and the mean total T3 concentration was 6.8 nmol/l, SD 2.73, range 3.1-17.5. For the group receiving T4 the mean total T4 concentration was 175 nmol/l, SD 25, range 150-258, and the mean total T3 concentration was 2.66 nmol/l, SD 0.45, range 1.7-4.2. In the hyperthyroid group a highly significant linear correlation was found between total T4 and total T3, T3 = 0.0354 T4 - 1.21, r = 0.761, P much less than 0.001, while in the patients taking T4 this correlation was less close, T3 = 0.0073 T4 + 1.39, r = 0.398, P much less than 0.001. The two groups are readily distinguished by expressing total T4 as a molar ratio of total T3. In the hyperthyroid group the mean T4:T3 ratio was 35.6, SD 7.8, range 19.9-56.1, compared to the patients on T4 where the mean T4:T3 ratio was 67.0, SD 11.7, range 44.3-114 (t = 22.5, P much less than 0.0001). An arbitrarily chosen value of 50 for the T4:T3 ratio affords a simple and convenient means of distinguishing the two categories: in only 3 patients with Graves' disease (2.6%) was the ratio above this, and it was below in only 5 patients (5.4%) taking T4.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Serum calcium concentration in hyperthyroidism at diagnosis and after treatment.
In a large, mainly outpatient, series of hyperthyroid patients who attended a district general hospital the serum concentrations of calcium and albumin were measured before and in many cases after treatment. The calcium level (mean +/- SD) before treatment (2.41 +/- 0.21 mmol/l, n = 437) was significantly higher (P less than 0.01) than afterwards (2.36 +/- 0.15 mmol/l, n = 232) and the albumin level rose when the patients became euthyroid (from 40.5 +/- 3.1 g/l to 44.0 +/- 2.4 g/l; P less than 0.01). After treatment neither value differed from those of an unselected group of out-patients. The usual relation between the serum concentrations of calcium and albumin did not hold in the hyperthyroid subjects but reverted to normal on treatment; the variation, probably due to an increase in ionized calcium, leads to an overestimate of the 'corrected calcium' when conventional methods are used to calculate this figure. Thus, using a conventional formula 8.5% of our hyperthyroid patients would appear to have a calcium greater than 2.65 mmol/l (normal mean plus 2 standard deviations) whereas using a correction factor specific for the hyperthyroid situation the figure is reduced to 5.7% which is only twice the expected proportion. The calcium level was significantly greater (P less than 0.001) in those patients in whom initial T3 concentration was high (greater than 7.2 nmol/l). There was no effect of T4 upon serum calcium which could not be accounted for by the action of T3. In this series of 437 patients there was no case of symptomatic hypercalcaemia. The maximum value was 2.80 mmol/l in a patient with coincident primary hyperparathyroidism. Significant hypercalcaemia is rare in hyperthyroidism.
Adolescent↗
Thyroid function and immunological activity during and after medical treatment of Graves' disease.
The variable clinical course of Graves' disease has been followed in 27 patients each studied for 2 years from the time of diagnosis. Thyroid hormone synthesis was blocked with large doses of antithyroid drugs for the first 12 months while euthyroidism was maintained with triiodothyronine. The latter was given alone from 12 to 18 months, and for the last 6 months the patients received no treatment. The activity of the disease was determined by repeated measurements of thyroid uptake of pertechnetate and by assay of thyrotrophin receptor antibodies (TSH binding inhibitory immunoglobulins). Retrospectively there were no features on presentation which singly or in combination indicated the clinical outcome: 16 patients remained in remission (Group 1) whilst in 11 hyperthyroidism had recurred before the end of the study (Group 2). Both measures of disease activity (thyroid uptake and antibody levels) fell during the first 12 months in patients of both groups. Recurrence of Graves' disease could be predicted in some but not all patients of Group 2 at 12 months by higher thyroid uptakes and levels of thyrotrophin receptor antibodies. There was, however, evidence of abnormal thyroid function, from which we infer continuing activity of the disease, 12 to 18 months after diagnosis in all patients of Group 1, even though these patients had normal TRH tests during the last phase of the study. The difference in the course of Graves' disease 12 to 24 months after diagnosis between those patients who remained in remission and those who did not was relative: in no patient was completely normal physiological control of thyroid function re-established. Clinical remission from hyperthyroidism at this time is a level of disease activity at which the normal physiological output of thyroid hormones is not exceeded.
Carbimazole↗
Consistency and variability in the character of thyrotrophin receptor antibodies in Graves' disease.
At diagnosis there was no correlation between the uptake of pertechnetate by the thyroid and thyrotrophin receptor antibodies (TRAb) measured as TSH binding inhibitory immunoglobulins in a series of 27 patients with Graves' disease. TRAb were detectable initially in 19 patients, in 11 of these there was a significant positive correlation (P less than 0.05) between serial measurements of pertechnetate uptake and TRAb made during 2 years following diagnosis. In five patients pertechnetate uptake fell with time whilst TRAb levels were maintained or fluctuated. In the remaining three of the 19 patients both measurements were low and did not change during treatment. We conclude that TRAb in any individual patient are a mixture of immunoglobulins of variable effectiveness as thyroid stimulators. In a majority of patients the composition of this mixture remains constant during the course of the illness and the clinical state reflects the levels of TRAb in the blood. In a minority, however, the character of these antibodies may alter with time or there is a change in the responsiveness of the thyroid gland. The general lack of correlation between measurements of thyroid stimulating activity and TSH binding inhibitory immunoglobulins in groups of patients is due to differences between patients in the composition of TRAb.
Female↗
Free thyroid hormone concentrations in subjects with various abnormalities of binding proteins: experience with amerlex free-T4 and free-T3 assays.
Free thyroid hormone concentrations measured by Amerlex assays were studied in subjects with inherited disorders of thyroxine-binding globulin (TBG) synthesis, variant albumins with a high avidity for T4, and iodothyronine-binding autoantibodies. Free T4 (fT4) and free T3 (fT3) levels were normal in euthyroid subjects with TBG deficiency and excess. Free T3 concentration was in the low normal range in subjects having a variant albumin but fT4 (Amerlex) was erroneously elevated because of the enhanced affinity of the 125I-T4 analogue employed in the assay for the abnormal albumin. The 125I-T3 analogue used in the fT3 assay does not bind more strongly to this variant albumin than to normal albumin. Amerlex assays for fT4 and fT3 in patients with iodothyronine-binding autoantibodies to thyroglobulin give variable results according to the specificity of the autoantibodies: non-specific antibodies cause extraordinarily high values even in hypothyroid patients; fT3 measurements may be appropriate in patients with T4-specific antibodies and even in some with T3-specific antibodies. The presence of such antibodies should be suspected if the results of Amerlex assays for fT4 and fT3 are discordant or are inconsistent with the clinical picture or TSH levels.
Autoantibodies↗
Hyperthyroxinaemia: abnormal binding of T4 by an inherited albumin variant.
Two euthyroid subjects with high total concentrations of T4 in their sera have been studied (J.D.: T4, 170; T3, 1.90; rT3, 0.54 nmol/l. E.T.: T4, 185; T3, 1.63; rT3, 0.37 nmol/l). Concentrations of all three T4-binding proteins were within normal limits in both cases. However, on reverse-flow electrophoresis an abnormally large amount of thyroxine was found to travel with albumin. The three T4-binding proteins in the sera of both patients were separated from each other by a novel affinity chromatographic method using dye-Sepharose conjugates. Affinity constants for T4 binding to TBG and to prealbumin from both patients were normal. The albumin preparations were further purified and shown by physical and immunochemical techniques to be uncontaminated by other proteins. Scatchard plots of the binding of T4 to each of these pure albumins revealed two components, one having a normal affinity constant (J.D., 1.8 x 10(5) lmol-1 and E.T., 2.3 x 10(5) lmol-1), the other having a raised affinity constant (J.D., 5.4 x 10(6) lmol-1 and E.T., 5.8 x 10(6) lmol-1). Extrapolation of the plots showed that the high affinity components comprised 66% (J.D.) and 54% (E.T.) of the total purified albumin. The raised affinity and high concentrations of the variants thus account for the raised total T4 concentrations in the patients. The presumed amino acid substitution in the albumins may be different in the two patients since the affinities for rT3 differ. Some methods for the estimation of free T4 levels give misleading results in the presence of these albumin variants. In the course of two episodes of illness, patient J.D. manifested large falls in serum T4 levels which could only be accounted for by reduced carriage of T4 by the abnormal and conventional binding proteins. Many cases reported in the literature as partial peripheral resistance to thyroid hormone may be examples of similar albumin variants.
Adult↗
Increased serum concentration of T4-binding globulin in patients with hypogammaglobulinaemia.
Patients with hypogammaglobulinaemia have been regularly found to have abnormal conventional thyroid function test results. The abnormality is due to an increased plasma concentration of T4-binding globulin (TBG). As the prevalence of autoimmune thyroid disease is probably increased in hypogammaglobulinaemia this further abnormality in the plasma proteins may lead to diagnostic confusion. Administration of gammaglobulin by infusion causes a rapid but transient fall in plasma concentrations of TBG and T4 which is probably due to a temporary redistribution of the plasma proteins.
Agammaglobulinemia↗
An intracranial metastasis from a PRL secreting pituitary tumour.
A 70-year-old man developed panhypopituitarism and was found to have hyperprolactinaemia and a locally invasive pituitary tumour. The visual fields were unaffected and therefore the patient was treated with hormone replacement only. After 3.5 years during which time the pituitary tumour had not enlarged further, the patient developed a mass in the left cerebello-pontine angle. This mass was subsequently shown to be entirely separate from, but histologically identical to, the pituitary tumour and the cells of both contained PRL. Evidence was obtained to show that the tumour had spread by a vascular route. This is the second reported case of a malignant prolactinoma.
Adenoma, Chromophobe↗
Restricted antigenicity of thyroxyls in human thyroglobulin.
Interactions between two human iodothyronine-binding autoantisera and three preparations of human thyroglobulin (Tg) were not proportional to the latter's thyroxyl residue content. Probably only one of the several thyroxyl-containing sites in Tg reacted with the immunoglobulins from both antisera. In the case of one of the antisera, which was thyroxine (T4)-specific, the thyroxyl residue was the immunodominant feature of the antigenic site. The other antiserum, which had a specificity for 3,5,3'-tri-iodothyronine (T3), recognized different determinants around the same thyroxyl residue, but this residue was not itself an important element of the binding site. Thus, despite the specificity for T3 free in solution, the presence of T4 in the complete antigenic site was tolerated, since other structures supplied the bulk of the binding energy. 'Specificity' of this antiserum for T3 in solution is therefore coincidental and need not be ascribed to the presence of T3 in the original immunogen. Some results obtained in these studies may be interpreted as supporting the possibility that a modified Tg was the immunogen for the generation of these naturally occurring human antisera.
Animals↗
Thyroid hormones and the regulation of thyroid function in men with coeliac disease.
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Adolescent↗
Re-evaluation of results when determining thyroid stimulating immunoglobulins in serum.
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Humans↗