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G C Schussler

Publications and source records attributed to G C Schussler.

At least 19 recordsLinked to original sources
PubMed2001

Cleavage of thyroxine-binding globulin during cardiopulmonary bypass.

Thyroxine-binding globulin (TBG) is a noninhibitory member of the serine protease inhibitor (serpin) superfamily. A characteristic serpin cleavage product of TBG has been demonstrated in sera of septic patients. We find that a similar cleavage product appears in serum during the rapid decline of immunoassayable TBG and thyroxine (T(4)) that is associated with the inflammatory response to cardiopulmonary bypass (CPB). In vitro cleavage of TBG by the serine protease, neutrophil elastase induces a conformational change that has previously been shown to weaken affinity for T(4.) In vitro protease cleavage also decreases immunoassayable TBG, probably because the conformational change decreases the availability of the TBG epitopes to the measuring antibody. Thus, the rapid decrease in immunoassayable TBG concentration previously attributed to accelerated clearance is caused in part by the proteolytic cleavage per se. The evidence for proteolysis of TBG concurrent with the decrease in serum T(4) during CPB is consistent with the proposed release of T(4) from TBG to cells showing serine protease activity.

Cardiopulmonary Bypass↗
PubMed2000

Selective consumption of thyroxine-binding globulin during cardiac bypass surgery.

A study of serum thyroid hormone binding proteins and thyroid hormone concentrations during and after coronary artery bypass graft (CABG) surgery shows a marked difference in the response of thyroxine binding globulin (TBG) and transthyretin (TTR). The effects of CABG on TBG and TTR were compared in 32 patients during the day of surgery. In a few of these patients, additional determinations were performed to 5 days. When corrected for dilution, TTR concentrations decline gradually after surgery, with no significant decrease over the first 24 hours. In contrast, a rapid decrease of TBG to a mean level of 60% of the preoperative control at 12 hours after the start of surgery appears to account for the concomitant decrease of serum T4. The rate at which the TBG concentration decreased far exceeds the reported fractional clearance of TBG and therefore implies accelerated consumption rather than inhibition of production. TBG is a member of the serine protease inhibitor (SERPIN) superfamily. We propose that its rapid consumption is due to protease cleavage at inflammatory sites. This may explain the previously observed accumulation of thyroxine iodine at such sites.

Adult↗
PubMed2000

Concordant decreases of thyroxine and thyroxine binding protein concentrations during sepsis.

The principal thyroxine (T4) binding proteins were measured in 8 septic patients and 8 controls to determine the extent to which a decrease in their concentration contributes to the decrease in serum T4 in sepsis. T4 binding globulin (TBG) evaluated by radioimmunoassay (RIA) and radial immunodiffusion (RID) was 61% and 66%, respectively, of the normal mean value in sera from septic patients. Decreases of albumin and transthyretin (TTR) to 55% and 29%, respectively, of the normal mean concentration contributed to the loss of T4 binding power in these sera. Total serum binding of T4, calculated from the normal contribution of each protein to T4 binding and the reduction of its concentration in septic patients, was 55% of that in the normal controls. This decrease in the estimated protein binding of T4 was proportional to the decrease of serum T4 from a mean of 8.4 microg/dL in the normal controls to 4.7 microg/dL (56% of the control) in the septic patients. Because TBG binds most of the serum T4, the decrease in the TBG concentration was the major factor in the decrease of total T4 binding power. Since the concentration of the major T4 binding proteins decreased sufficiently to account for the decrease in serum T4, it is unnecessary to postulate the effects of additional factors such as binding inhibitors or modification of T4 binding protein affinity.

Adult↗
PubMed2000

The thyroxine-binding proteins.

The slow clearance, prolonged half-life, and high serum concentration of thyroxine (T4) are largely due to strong binding by the principal plasma thyroid hormone-binding proteins, thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin. These proteins, which shield the hydrophobic thyroid hormones from their aqueous environment, buffer a stable free T4 concentration for cell uptake. Free rather than bound T4 is subject to homeostatic control by the hypothalamic-pituitary thyroid axis. Although it is not a protease inhibitor, sequence analysis identifies TBG as a member of the serine protease inhibitor (serpin) family of proteins. Proteolytic cleavage of TBG appears to be a mechanism for site-specific release of T4 independently of homeostatic control. TBG probably facilitates the transport of maternal T4 and iodide to the fetus, although this remains to be proven. High-affinity cellular binding sites for TTR have been described; however, their function and that of choroid plexus synthesis of TTR and transport of T4 into the cerebrospinal fluid remain unclear. Albumin, with the lowest T4 affinity and fastest T4 release of the major T4-binding proteins may promote quick exchange of T4 with tissue sites. The affinity of albumin for T4 is increased by histidine substitution for arginine 218 in the most common form of dysalbuminemic hyperthyroxinemia. However, proline and alanine substitutions at the same site have a similar effect, suggesting that arginine 218 interferes with T4 binding.

Aging↗
PubMed2000

A characteristic serpin cleavage product of thyroxine-binding globulin appears in sepsis sera.

T4-binding globulin (TBG), the principal thyroid hormone-binding protein of serum, is a member of the serine protease inhibitor (serpin) superfamily. We report a characteristic serpin cleavage product of TBG in sepsis sera. At 49-50 kDa, the TBG remnant is 4-5 kDa smaller than the intact protein and is the same molecular mass as a TBG cleavage product produced by incubation with polymorphonuclear elastase. Incubation with polymorphonuclear leukocytes also produces the 49- to 50-kDa remnant, and this proteolysis is stimulated by zymosan activation. Polymorphonuclear cell cleavage of TBG increases the ratio of free/bound T4. As previously described, in vitro cleavage of TBG by elastase also increases free/bound T4. These findings are consistent with the hypothesis that serine proteases present at inflammatory sites cleave TBG, releasing its hormonal ligands.

Adult↗
PubMed1995

Rapid changes in thyroid function tests upon treatment of tuberculosis.

SETTING: Inpatient service and tuberculosis (TB) clinic of a public hospital. OBJECTIVES: (1) To test the hypothesis that an hepatic effect of antituberculosis drugs increases serum thyroxine-binding globulin (TBG); (2) to resolve conflicting reports on thyroid function in TB. DESIGN: Measurement of serum thyroid hormones, thyroid hormone binding (T3RU) and binding proteins (TBG, transthyretin [TTR] and albumin) in 38 patients with active TB and in 29 healthy tuberculin-positive controls, before and about 10 days into therapy. RESULTS: With therapy of TB (with isoniazid [INH], rifampin [RIF], ethambutol and/or pyrazinamide), TBG increased above control values and T3RU decreased (P < 0.001). These changes were weakly correlated with liver enzyme activities but did not predict clinical hepatitis, which developed in only 1 patient. T3 was initially subnormal in 61% of 38 TB patients, while T4, thyrotropin (TSH) and TBG were normal. T3, TTR and albumin, all negative acute phase reactants, increased towards normal by day 10 (P < 0.001). Thyroid function remained unaltered in 14 control patients taking INH, whereas T3RU decreased (binding increased) and T3 increased in 15 taking INH and RIF (P < 0.001). CONCLUSIONS: TB patients manifest the expected low T3 of non-thyroid illness, but, unlike most sick patients, usually have normal or increased serum binding of thyroid hormones. Chemotherapy further increases binding by increasing TBG, an effect probably due to RIF.

Antitubercular Agents↗
PubMed1995

Identification of a human serum albumin species associated with familial dysalbuminemic hyperthyroxinemia.

Familial dysalbuminemic hyperthyroxinemia (FDH) is a form of euthyroid hyperthyroxinemia that is due to an increased affinity of serum albumin for T4. Unlike the many physiologically neutral alloalbumins that have been identified by serum electrophoresis, FDH variants have not been reproducibly resolved. In the present study, isoelectric focusing in the presence of the denaturants urea and Nonidet P-40, without reduction, produced two bands in the sera of unrelated FDH subjects in place of each of the major albumin bands in the sera of normal subjects. One band of each FDH pair migrated with the normal band; the second migrated at a slightly lower pI. The identity of the new bands as albumin was confirmed by N-terminal sequencing. The two bands of each pair were present in approximately equal amounts, consistent with the autosomal dominant nature of the condition, the expectation that FDH individuals would be heterozygous for normal albumin (Alb-A), and evidence that high and normal affinity T4-binding sites are equimolar or near equimolar. Similar findings in sera from Hispanic and non-Hispanic FDH subjects suggest that the same structural change may underlie the FDH phenotype from different populations. The slightly lower pI of the FDH-specific bands is consistent with the His for Arg substitution predicted by a G to A base transition recently reported in codon 218 of the gene for the variant albumin (Alb-FDH).

Detergents↗
PubMed1995

Familial dysalbuminemic hyperthyroxinemia in pregnancy.

A 16-year-old pregnant Puerto Rican woman who had been treated for thyrotoxicosis previously was evaluated for goiter, increased total thyroxine (T4) and triiodothyronine (T3) and free T4 estimate, despite a normal thyroid-stimulating hormone (TSH) concentration. These findings are consistent with a TSH-producing pituitary adenoma or the syndrome of generalized thyroid hormone resistance. However, sera from the patient, her mother and subsequently her newborn daughter demonstrated the increased albumin binding of T4 but not T3 that is characteristic of familial dysalbuminemic hyperthyroxinemia (FDH). The free T4 estimate had been elevated artefactually by the increased affinity of FDH albumin for the analog in a one-step assay. The T3 and T4 concentrations were increased by pregnancy and T4 was increased further by FDH. This first report of FDH recognized during pregnancy emphasizes that the effects of pregnancy on thyroid hormone and TSH concentrations complicate the diagnosis of FDH. It is particularly important to distinguish this benign condition from thyrotoxicosis during pregnancy, because inappropriate treatment may affect fetal development.

Adolescent↗
PubMed1993

Thyroxine binding in a TTR Met 119 kindred.

Recently, a transthyretin variant, TTR Met 119, in which methionine substitutes for threonine 119, a component of the protein's iodothyronine binding site, was identified in individuals with transient euthyroid hyperthyroxinemia. Healthy carriers of Met 119 have normal serum thyroid hormone concentrations, but two studies of Met 119 carriers have differed as to whether T4 binding to TTR is increased. An additional kindred has been identified by hybrid isoelectric focusing in an ongoing screening program for TTR variants in the Portuguese population with TTR Met 30 associated familial amyloidotic polyneuropathy. Cyanogen bromide peptide mapping and DNA restriction length polymorphism analyses showed that the propositus was a compound heterozygote for two TTR variants: Asn 90 and Met 119. Family analysis revealed that he inherited the TTR Met 119 variant from the mother and the TTR Asn 90 variant from the father. Neither the compound heterozygote nor his parents had symptoms of familial amyloidotic polyneuropathy. Serum dialysis with stepwise saturation of iodothyronine binding sites confirmed that TTR binding of T4 is increased in TTR Met 119. The increased binding is due to a higher TTR concentration rather than an increased association constant for T4. Because of the small proportion of serum T4 bound by TTR, increased T4 binding by TTR did not affect the ratio of free to bound T4 or T4 concentrations. In contrast, plasma retinol binding protein, almost all of which is bound by TTR, was elevated. The Asn 90 mutation does not affect either the concentration or the hormone binding characteristics of the protein. Possible long-term effects of these mutations and the combined heterozygotic state remain to be determined.

Amyloidosis↗
PubMed1990

Receptor-mediated uptake and internalization of transthyretin.

Evidence of cellular transthyretin (TTR) binding was sought because of the observation that transthyretin can increase the uptake of its hormonal ligand. Transthyretin was bound by human hepatoma (Hep G2) cells in a time- and temperature-dependent manner, reaching equilibrium within 2 h. Scatchard analysis was consistent with a single class of high affinity binding sites with a Kd of approximately 5 nM at 0 and 4 degrees C and 14 nM at 37 degrees C. These dissociation constants are more than 2 orders of magnitude lower than the concentration of transthyretin in human serum. The apparent capacity at 0 degrees C, corrected for internalized TTR, was approximately 20,000 sites/cell. Saturable, high affinity binding of human transthyretin was also demonstrable with rat primary hepatocytes and human renal adenocarcinoma, neuroblastoma, and transformed lung cells. Rat and human transthyretin were equipotent in displacing isotopically labeled, species-specific transthyretin from human hepatoma cells and rat primary hepatocytes, a finding that is consistent with the strong homology between rat and human transthyretin. Eighty-eight percent of the saturable uptake was internalized as determined by proteolytic removal of surface transthyretin. Internalization was dependent on receptor binding and was more markedly inhibited than surface binding at 0 degrees C. Concentrations of thyroxine within a range that saturated a significant proportion of the primary and secondary TTR iodothyronine binding sites increased the uptake and internalization of transthyretin in a dose-dependent manner. By analogy to the function of receptors for other transport proteins, the interaction between transthyretin and its receptor is likely to affect ligand delivery and may have additional metabolic effects.

Animals↗
PubMed1990

Studies on the nature of iodothyronine binding in familial dysalbuminemic hyperthyroxinemia.

The effects of pH and anionic binding inhibitors were used to test the hypothesis that the increased T4 binding affinity of the variant albumin (Alb-FDH) of familial dysalbuminemic hyperthyroxinemia (FDH) is due to an electrostatic bond with the ionized phenolic hydroxyl of the iodothyronine. As determined by charcoal adsorption from 2% serum in which binding to T4-binding globulin and transthyretin had been inhibited, increased T4 binding by Alb-FDH was pH dependent and proportional to the ionization of the phenolic hydroxyl. Increased T3 binding became apparent above physiological pH, as is consistent with the higher pK of the T3 phenolic hydroxyl. The iodothyroacetic analogs of T4 and T3 developed maximal increases in binding to Alb-FDH at about the same pH as the corresponding iodothyronines. Aspirin, salicylate, warfarin, and chloride, anions that have minimal stereochemical resemblance to the iodothyronines but bind to albumin cationic groups, inhibited T4 binding to FDH sera at concentrations that had little or no effect on binding in normal sera. Increased displacement of T4 from Alb-FDH by salicylate was also evident at therapeutic ratios to a 1:1 dilution of serum in a dialysis system. Aspirin displaced T4 at a lower pH than T3, as is consistent with competition with the ionized iodothyronine phenolic group. These findings suggest that an electrostatic bond between the iodothyronine phenolate and a cationic group on the protein is the basis for the increased affinity and specificity of Alb-FDH for T4.

Aspirin↗
PubMed1990

Transthyretin receptors on human astrocytoma cells.

Transthyretin (TTR), a transport protein for T4 and retinol-binding protein, is the principal T4-binding protein of cerebrospinal fluid. Its function in regard to the delivery of its ligands and in other respects is unclear. The binding of [125I] TTR to cultured human astrocytoma cells was studied to determine whether these cells carry receptors for TTR. Scatchard analysis was consistent with a single class of binding sites with a Kd of 3 nM. No significant cross-reactivity with transferrin or serum albumin was observed. Internalization of TTR was temperature dependent and proportional to receptor occupancy. Dilutions of cerebrospinal fluid displaced [125I]TTR in proportion to their content of radioimmunoassayable TTR and in parallel with purified TTR. The uptake and internalization of TTR increased in the presence of high T4 or T3 concentrations. These results demonstrate that TTR binds to specific high affinity receptors on human astrocytoma cells. Receptor binding of TTR provides a potential mechanism for the delivery of its ligands within the central nervous system.

Astrocytoma↗
PubMed1989

Increased serum cortisol binding in chronic active hepatitis.

PURPOSE: A high serum cortisol concentration, apparently due to increased cortisol-binding globulin (CBG), was found in a patient (index case) with chronic active hepatitis (CAH). We therefore performed further studies to determine whether increased cortisol binding is generally associated with CAH. PATIENTS AND METHODS: Serum samples were obtained from 15 hospitalized patients with long-term liver function test elevations but no evidence of cirrhosis, 15 normal subjects without a history of hepatitis, four healthy pregnant women, and 10 alcoholic patients with stigmata of cirrhosis. Serum cortisol binding was measured by an adaptation of a previously described charcoal uptake method. Thyroxine-binding globulin (TBG) and sex hormone-binding globulin were determined by radioimmunoassays. RESULTS AND CONCLUSION: Charcoal uptake of 125I cortisol from sera of normal subjects and additional patients with CAH revealed that increased serum cortisol binding by a saturable site, presumably CBG, was associated with CAH. Cortisol binding was significantly correlated with immunoassayable TBG, suggesting that in CAH, similar mechanisms may be responsible for increasing the serum concentrations of CBG and TBG.

Adult↗
PubMed1985

Triiodothyronine increases serum angiotensin converting enzyme.

To determine whether elevated thyroid hormone is responsible for increased serum angiotensin converting enzyme in hyperthyroidism, 5 to 40 micrograms of 3,5,3'-triiodo-L-thyronine was administered orally and subcutaneously to female Swiss-Webster mice. Serum angiotensin converting enzyme was significantly increased in all animals given triiodothyronine compared to controls. Lung and kidney enzymes were moderately reduced in specific activity but unchanged in total activity due to increase in size of these organs. The results indicate that in hyperthyroidism, elevated thyroid hormone per se rather than the disease of the thyroid is responsible for elevated serum angiotensin converting enzyme.

Animals↗
PubMed1985

Components of the total serum thyroid hormone concentrations during pregnancy: high free thyroxine and blunted thyrotropin (TSH) response to TSH-releasing hormone in the first trimester.

The distribution of thyroid hormones between free solution and their several protein-binding sites during pregnancy was studied under physiological conditions of temperature and pH. Single serum specimens were obtained from individual women at different stages of pregnancy. During the first 5 weeks of pregnancy, mean serum free T4 and free T3 concentrations were 50% higher than in nonpregnant women or women during the third trimester. Free T4 was increased significantly throughout the first trimester, but because of wide variance, free T3 was significantly above control values only during the first 5 weeks. Free T4 and free T3 concentrations decreased to control levels in the third trimester. These changes in free T4 concentrations are consistent with a weak thyrotropic action of hCG, which attained maximal concentrations early in the first trimester and then decreased markedly in the second and third trimesters. TRH testing of women scheduled for abortion in the first and second trimesters revealed marked inhibition of TSH response to TRH in those first trimester women who had elevated free T4 concentrations. The percent free T4 did not decrease during the first 5 weeks, but then declined progressively to term as T4-binding globulin (TBG) affinity, defined as the product of the capacity and affinity constant, progressively increased. T4 bound to TBG (T4-TBG) increased from early in the first trimester to term, and then decreased in postterm pregnancy and postpartum. T4 bound to prealbumin (T4-PA) and to albumin (T4-Alb) decreased significantly in the third trimester compared with either control or first trimester concentrations. The concentration of free T3 was positively correlated with T4-PA (r = 0.25) and T4-Alb (r = 0.31), but not with free T4 (r = 0.18) or T4-TBG (r = -0.30) concentrations. These results suggest that 1) only the high concentrations of hCG present in the first trimester of pregnancy have a thyrotropic effect in excess of normal levels of TSH, and this can be sufficient to suppress the TSH response to TRH; 2) hepatic TBG secretion continues to respond to the continuously rising estrogen levels throughout pregnancy; and 3) T4-PA and T4-Alb, but not free T4 or T4-TBG, are possible precursors for the extrathyroidal generation of T3.

Chorionic Gonadotropin↗