Biomedical subjects
Publications and source records attributed to H Meinhold.
The ex vivo model which reflects hemodialysis modulating factors during the first twenty minutes of blood membrane interaction, is applicable as a pre-clinical test for new membranes. The biocompatibility of a new cellulosic membrane (MC) proved to be superior to regenerated cellulose and comparable to synthetic membranes such as PAN regarding complement activation.
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In the present study we reviewed 230 patients in whom thyrotropin-binding inhibiting antibodies (TBIAb) follow-up determinations had been performed up to 10 yr after hyperthyroidism had first developed. In 104 patients, Graves' ophthalmopathy occurred at some time in the course of the observation period. Fourty-four of these patients with Graves' ophthalmopathy had at least one, and up to four relapses after each one-year course of antithyroid drug therapy with methimazole. The addition of TBIAb-positive results over an observation period of 1-10 yr showed positive cumulative findings in 95% of the 44 patients with recurrences of Graves' disease. A single TBIAb determination during hyperthyroidism showed positive results in 70%. A detailed breakdown showed that TBIAb was detectable during all hyperthyroid phases in 48% of the patients with ophthalmopathy. Thirty-four per cent of the patients had sometimes positive, sometimes negative TBIAb findings in the various hyperthyroid states. In 18% of the patients, TBIAb was not detected in any of the hyperthyroid phases. However, some of these patients became TBIAb-positive for the first time during antithyroid drug therapy or during a remission confirmed by a suppression test. Only 2 of the 44 patients never had TBIAb positive results at any time during the observation period. In those patients without ophthalmopathy during the observation period, the "cumulative" frequency of TBIAb was 74% for patients with diffuse goiter and 52% for patients with diffuse-nodular goiter. However, in patients with ophthalmopathy, there was no difference in TBIAb detectability between those patients with a diffuse and those with a diffuse-nodular thyroid.(ABSTRACT TRUNCATED AT 250 WORDS)
Several methodological aspects concerning the measurement of thyroid-stimulating antibodies (TSAb) were examined using a 5000-g particulate fraction from human thyroid tissue. TSH displayed maximal stimulation at 32 C. An ATP-regenerating system had no influence at ATP concentrations greater than 0.67 mM. Theophylline did not influence cAMP concentrations in the incubation medium after stimulation with increasing dosages of TSH, suggesting the absence of active phosphodiesterases in the membrane preparations. Sera dialyzed against Tris-HCl were as suitable as immunoglobulin G preparations for determination of TSAb. One hundred and nineteen patients with ophthalmic Graves' disease, 42 of whom were hyperthyroid at the time of study, were investigated for TSH binding-inhibiting antibodies ( TBIAb ) and TSAb. In 76% of these patients, concordance between the presence and absence of both activities was found independent of whether they were untreated, treated, or in remission. When gradations of potency in the two systems were compared, linear regression revealed a correlation coefficient of 0.59. The coefficient correlation increased when TBIAb and TSAb were each determined in a single assay using identical thyroid membrane preparations. In four other patients, both TSAb and TBIAb were measured repeatedly during the course of the disease. In three patients, both activities were parallel, whereas in one patient, dissociation of the two activities was found. The data suggest the presence of antibodies with varying stimulating and binding-inhibiting properties. However, in hyperthyroidism of Graves' disease, both activities usually were present in similar quantities.
In 36 patients, intraoperative peritoneal lavage with PVP-iodine solution (26 patients) or with the iodine free chemotherapeutic agent Taurolin (10 patients) was performed because of peritonitis. Total iodine serum levels increased considerably after peritoneal lavage with PVP-iodine. In the early postoperative phase, the resorbed iodine was mostly present as iodide in serum. Iodine serum values returned to normal after 30 days. A decrease in T4 and T3 could be observed with a concomitant reciprocal increase of rT3 in the acute phase of peritonitis. Normalization of the thyroid hormone took place after 8 days. A stronger increase in T4 occurred temporarily in 2 of 5 patients known to have thyroid function disorders. These changes in thyroid hormone may also be considered as the consequence of the severe primary disease. Normalization of hormone values was clearly delayed after PVP iodine lavage. The possible risk of an iodine-induced thyrotoxicosis after intraperitoneal application of PVP-iodine is pointed out, and objections are made to using this therapy.
One hundred fifty patients with toxic and scintigraphically diffuse goiter were HLA typed (A, B, C, DR). One group consisted of 101 patients with concomitant Graves' ophthalmopathy and/or TSH-binding inhibiting antibodies (TBIAb). Forty nine patients had neither ophthalmopathy nor TBIAb. The former group showed a higher prevalence of HLA-B8 and DR3 compared to a normal control group. The latter group showed a higher frequency of HLA-DR5, whereas the HLA-B8 and DR3 antigens were slightly below normal prevalence. These data indicate an immunogenetic heterogeneity in patients with toxic diffuse goiter. A group of 47 hyperthyroid patients with single autonomous thyroid adenoma had no increased prevalence of any HLA-antigens. Patients with long term remission did not show an altered prevalence of any of the HLA antigens compared to controls. In contrast, patients with Graves' ophthalmopathy and/or TBIAb activity who relapsed had a significantly higher prevalence of HLA-B8 DR3, whereas patients without TBIAb and eye signs who relapsed had a significantly higher prevalence of HLA-DR5 than the control group.
The thyroid function of 13 patients with proteinuria and normal serum creatinine level (Group 1) and 15 patients with proteinuria and increased creatinine level (Group 2) was investigated. The daily urinary T41- and T3 excretion was much higher in Group 1 patients than in Group 2 patients (37.1 +/- 25.9 nmol T4 vs 17.5 +/- 8.7 nmol T4, 3.3 +/- 1.6 nmol T3 vs 1.1 +/- 0.8 nmol T3, respectively) and correlated in both groups with the protein loss. None of the patients suffered from hypothyroidism as a consequence of this hormone loss. Although the mean serum T4-, T3-, FT4-, FT3-, TBG- and TBPA concentrations in both groups of patients were within the normal range, the urinary hormone loss appeared to influence these values considerably. It was striking that the rT3 concentration in the patients with the highest hormone loss was frequently less than 0.08 nmol/l, the lower limit of detectability. The basal TSH levels in serum of the nephrotic patients were similar to those of normal individuals. The thyroid function of patients with proteinuria accompanied by retention of creatinine due to renal failure was more difficult to assess because different pathological mechanisms may exert their influence on the thyroidal hormone secretion as well as on the peripheral hormone metabolism.
Serum concentrations and metabolic clearance rates (MCR) of diiodotyrosine (DIT) and thyroxine (T4) have been measured by radioimmunoassay and tracer kinetic technique in both normal rats and rats treated with 3-nitro-L-tyrosine (MNT), a potent inhibitor of iodotyrosine deiodinase. In normal rats, DIT serum levels were 0.27 +/- 0.12 nmol/l (mean +/- SD); MCR was 15.9 ml/h . 100 g body weight (bw), and the turnover rate was 4.3 pmol/h . 100 g bw. Inhibition of iodotyrosine deiodination by treatment with 50 mumol MNT per day for 1 week caused a highly significant elevation of DIT serum levels to 4.80 +/- 3.30 nmol/l, a decrease of MCR to 9.0 ml/h . 100 g bw and a ten-fold increase of the DIT turnover rate to 43.2 pmol/h . 100 g bw. Serum concentrations of T4 and T3 decreased slightly, whereas the T4 turnover rate (37.5 vs 37.8 pmol/h . 100 g bw) and rT3 serum levels remained unchanged under MNT treatment. The study demonstrates the presence of measurable DIT serum concentrations in the normal rat. Inhibition of intra- and extrathyroidal iodotyrosine deiodinase leads to a situation in which circulating iodotyrosines play an equally important role in peripheral iodine turnover as the iodothyronines. Since DIT serum levels in normal and enzyme-blocked rats were comparable to those in normal human subjects and patients with iodotyrosine deiodinase defect respectively, MNT-treated rats afford a suitable experimental model for this disease.
A review is made of methodical aspects of the performance of radioimmunoassays with special regard to the determination of T3, T4, TSH and free thyroxine. The quality of the analytical systems is determined by specificity, sensitivity, correctness and accuracy. To ensure quality, guidelines are given for the procedure of obtaining test samples as well as for the transport and storage; furthermore, the dependence of the results on the employed method is documented. For determination of the normal range particular emphasis has to be given to the methodical details, regional differences and the age of the patients. To ensure quality, the most frequent sources of error have to be known. These are listed for the determination of thyroid hormones, TSH, thyroxine-binding globulin, thyroglobulin and for the T3U-test; a critical review of the methods is added. Suggestions are given for the systematic internal control of quality; a method for continuous control by a computer program is presented.
The radiographic contrast agents commonly used for oral cholecystography have diverse effects on thyroid hormones in man. They may: (i) decrease serum triiodothyronine (T3) and increase reverse T3 in both hyperthyroid and euthyroid subjects, an effect attributable to inhibition of phenolic (outer) ring deiodination of iodothyronines; (ii) acutely increase serum thyroxine (T4) by displacing it from the liver, so inviting an erroneous diagnosis of hyperthyroidism; (iii) precipitate hyperthyroidism in apparently euthyroid subjects who have autonomous thyroid tissue. In comparison with the cholecystographic agents which are taken up by the liver, the renally-excreted contrast agents used for angiography or intravenous urography are much less potent in producing these effects. The paradox of T4 excess with normal T3 may arise after cholecystography, either by an acute T4 increase in a euthyroid subject, or by normalization of T3 in hyperthyroidism, thus creating a diagnostic dilemma. The recent trend towards use of oral cholecystographic agents in the urgent management of hyperthyroidism, because of their effect on serum T3, needs to be regarded with caution in view of the risk that hyperthyroidism may eventually be worsened if synthesis of T4 is not effectively blocked. For this reason, contrast media should probably be used in the treatment of hyperthyroidism only in conjunction with conventional antithyroid drugs. A history of exposure to contrast media should be sought in any acute or unexpected exacerbation of hyperthyroidism, or when T4 excess is found without an increase in T3.
In 69 hyperthyroid patients with diffuse uptake in the scintigram, thyrotropin displacing antibodies (TDA) were measured before, during and after thyrostatic treatment. In a further 42 patients antibody activity was investigated before and 6-12 weeks after radio-iodine treatment, and in 29 patients it was measured before and after subtotal thyroidectomy. Persistence of demonstrable TDA during and after the end of drug treatment was in all cases indicative of recurrence of hyperthyroidism. On the other hand, disappearance of TDA activity was not a guarantee for prolonged remission as five patients had a recurrence despite loss of TDA activity. In a further nine patients hyperthyroidism reappeared with recurrence of TDA after varyingly long periods of remission. Thyrostatic treatment should be performed until disappearance of antibodies. Prolonged demonstration of TDA should lead to surgical intervention. Besides the usefulness in establishing the diagnosis of immunogenic hyperthyroidism (Graves' disease) TDA estimation may be of some prognostic value in the use of thyrostatics. In contrast, after radio-iodine treatment or operation the functioning capacity of the remaining thyroid tissue seems to be more relevant for the success of treatment than the possibly longer acting antibodies.
20 Normal glands obtained from euthyroid subjects at autopsy were analysed for total iodine (Tl), PBl, L-thyroxine (T4), 3,3',5-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), 3,3'-diiodothyronine (T2) after pronase hydrolysis. The mean Tl was 325.1+-47.2 micrograms/g wet tissue, giving a total iodine per gland of 10.01 mg. Pretreatment of iodine containing X-ray drugs in 8 patients did not significantly affect these results with the exception of Lipiodol. The mean T4, T3 and T2 values were 93.0+-23.1 micrograms/g, 5.25+-0.99 micrograms/g, 5.54+-1.05 micrograms/g and 0.60+-1.19 micrograms/g, respectively. In contrast to goitrous tissue, normal thyroid tissue showed no dependence of the T4/T3 ratio on the Tl. Compared with goitrous tissue PBI consisted of much more T4-l in normal tissue. The corresponding values were 47.7+-11.8% and 12.7+-3.4%, respectively. A positive relationship was found between Tl and T4, T3, rT3 but not with T2. The rT3 concentration corresponds to that of T3 in a remarkable way. The ratios of T3 or rT3 were similar, suggesting that thyroidal T3 and rT3 production is a random process. T2 represents only 0.73% of T4-l. Our results in normal thyroid tissue clearly show that the difference in iodine concentrations is only one factor among others in comparison to goitrous tissue.
This report describes the application of a sensitive, specific, and reproducible RIA for diiodotyrosine (DIT) in human serum and metabolic studies on the source and kinetics of circulating DIT. Interference by cross-reactivity of T4 and other analogs was completely eliminated by isolation of DIT from serum with an efficient preparative immunoprecipitation technique. Mean (+/- SD) serum DIT levels were 161 +/- 133 pmol/liter (7.0 ng/100 ml) in 41 normal subjects, 64 +/- 30 pmol/liter in 46 pregnant women, 241 +/- 83 pmol/liter in the cord serum of 48 newborn infants, 542 +/- 494 pmol/liter in 22 hyperthyroid patients, and 101 +/- 71 pmol/liter in 15 hypothyroid patients. Mean values in pregnant, newborn and hyperthyroid subjects were significantly different from the normal mean. Very low DIT serum levels were found in four athyreotic patients during oral T4 substitution therapy, indicating that little DIT is formed by peripheral T4 degradation. In five normal subjects who received a single oral dose of 3 mg T4, serum DIT remained unchanged in one case and decreased in four cases. Radioimmunological measurements of DIT elimination from serum after the iv injection of 1 mg DIT in two normal volunteers gave MCRs of 103 and 133 liters/day and an average extrathyroidal DIT turnover rate of 19 nmol/day (8.2 microgram/day). These data indicate that circulating DIT arises predominantly from the thyroid, suggesting that peripheral formation of DIT is a minor metabolic pathway in the human.
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An international survey was conducted to study the performance of the radioimmunoassay of serum reverse triiodothyronine (rT3). Eight laboratories were provided with 10 serum samples containing several concentrations of rT3 and thyroxine (T4). Each laboratory also obtained the same batch of pure rT3. T4 and rT3 were measured by all participants in these samples. Half of the investigators routinely correct their data for T4 cross-reactivity. The results demonstrate that the performance of the rT3 radioimmunoassay is, on the average, satisfactory as judged from recovery experiments. Serum T4 influences the rT3 measurement to a lesser extent in the laboratories where corrections are performed compared with the others. Simple correction methods appear to fail, however, as the effect of a certain T4 concentration was found to vary with the rT3 level in the sample.
In the present study we tried to find out relationships between lung maturation-assessable by aid of lecithin concentrations in amniotic fluid-and fetal thyreoid gland function. In 256 pregnant women amniocentesis was done after 31/0 weeks of gestation, and concentrations of thyroxin, of reverse triiodothyronine and lecithins were measured. While thyroxin and lecithin concentrations proved not to be correlated, the rT3 and lecithin concentrations showed significant correlation (2 p less than 0.001). The curves measured were interpreted as signs of maturity of various organs (lung, thyreoid gland). We found out, that clinical value of measuring thyreoid gland hormones in relation to diagnosis of fetal maturation is of less importance.
Amniotic fluid concentrations of 3,3',5'-tri-iodothyronine (rT3), 3,3'-Di-iodothyronine (3,3'-T2), 3,5,3'-tri-iodothyronine (T3) and T4 were studied in 384 women during normal and complicated pregnancy. An inverse correlation was observed between decreasing rT3 and increasing 3,3'-T2 concentrations in amniotic fluid with gestational age. The mean rT3 level in normal pregnancy was 2.81 nmol/1 at 12-20 weeks and decreased significantly to 1.06 nmol/1 at 36-42 weeks of gestation. The mean 3,3'-T2 concentration was 49.1 pmol/1 at12-20 weeks increasing to 119 pmol/1 at 36-42 weeks. The mean T4 value of 3.83 nmol/1 at 12-20 weeks was about half that of later periods. The T3 concentration in a random sample of 45 amniotic fluids ranged from less than 28 to 370 pmol/1 (mean 102 pmol/1). The mean rT3, 3,3'-T2 and T4 values measured in patients with intra-uterine malnutrition, gestation diabetes, tocolysis, placental insufficiency and rhesus incompatibility at 31-40 weeks of gestation were not significantly different from those in uncomplicated pregnancy. Significantly decreased rT3 and T4 concentrations were found in toxaemia. From the results obtained in complicated pregnancy it may be concluded that measurements of iodothyronines, especially rT3, in amniotic fluid have insignificant diagnostic value in the recognition of intra-uterine lesions with the probable exception of fetal hypothyroidism. The analysis of the dependence of iodothyronine concentrations on the gestational age showed a maximum of rT3 and T4 levels between 20 and 30 weeks of pregnancy. This marked rise of iodothyronine concentrations in amniotic fluid at mid-gestation may be due to the onsetting maturation of the hypothalamic-pituitary-thyroid control system of the fetus.
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