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PubMed1988

Coexistence of familial dysalbuminemic hyperthyroxinemia with familial hypercholesterolemia and multiple lipoprotein type hyperlipidemia.

Familial dysalbuminemic hyperthyroxinemia (FDH), an autosomal disorder characterized by an increase in serum albumin binding of thyroxine, has been encountered in a family who was also found to have both familial hypercholesterolemia (FHC) and multiple lipoprotein type hyperlipidemia (MLH). One subject with FHC and two subjects with MLH had FDH. Although some of the laboratory parameters in hyperlipidemic patients with FDH were suggestive of hyperthyroidism, the dialyzable free thyroxine concentrations were in the normal range and the patients were clinically euthyroid. The significance of the occurrence of FDH in hyperlipidemic subjects with hypothyroidism has been discussed, especially in regard to the longer time interval that may be needed to achieve an amelioration of the hypothyroid state during treatment with a normal maintenance dose of thyroxine. Treatment of FDH patients with other drugs may require an altered dosage if the drug binds to the atypical albumin fragments characterizing this disorder.

Genes, Dominant↗
PubMed1996

Inhibition of serum protein binding of thyroxine in a hypothyroid patient with familial dysalbuminemic hyperthyroxinemia.

OBJECTIVE: To investigate unusual free thyroxine (FT4) responses to T4 replacement doses in a hypothyroid patient with familial dysalbuminemic hyperthyroxinemia (FDH). METHODS: In this FDH hypothyroid patient, serum FT4 concentration by equilibrium dialysis and T4, triiodothyronine (T3), and thyroid stimulating hormone (TSH) determinations were supplemented by thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA) measurements. RESULTS: Initial thyroid function tests were compatible with hypothyroidism and FDH (T4 = 78 nmol/L, T3 = 1.08 nmol/L, FT4 = 11.6 pmol/L, TSH = 45 mU/L). When she was initially treated with T4 (0.112-0.088 mg/day) there was an increase in FT4 concentration to hyperthyroid levels accompanied by TSH inhibition (FT4 = 31-51 pmol/L, TSH = <0.03 mU/L); the patient also complained of intolerance and nervousness, and T4 treatment was discontinued. Concentrations of thyroxine binding globulin (TBG) and thyroxine binding prealbumin (TBPA) were normal. When T4 therapy was later resumed at a dosage of 0.075 mg/day, there was a marked increase in percent dialyzable T4. The elevation in percent dialyzable T4 during T4 replacement in a patient with FDH is unusual in view of the very large T4 binding capacity of FDH albumin. The presence of an inhibitor that reduced T4 binding by both TBG and FDH albumin probably explains the elevation in percent dialyzable T4 during T4 treatment. CONCLUSIONS: This FDH patient represents the first case of a putative inhibitor of T4 binding to both TBG and FDH albumin. The inhibition of T4 binding by these disparate proteins suggests that the inhibitor effect is mediated nonspecifically.

Aged↗
PubMed2001

Congenital hypothyroidism in a child with unsuspected familial dysalbuminemic hyperthyroxinemia caused by a mutation (R218H) in the human albumin gene.

We found familial dysalbuminemic hyperthyroxinemia (FDH) in a 5-month-old boy with congenital hypothyroidism (CH) who had a blood thyrotropin (TSH) level of 479 mU/L but normal total serum thyroxine (T4) and higher than normal total triiodothyronine (T3) levels. Thyroid hormone substitution began at 5 weeks of age when T4 and T3 concentrations were below normal. Until the age of 5 months, treatment with levothyroxine was suboptimal on the basis of high serum TSH levels despite above-normal T4 levels. FDH was confirmed by isoelectric focusing and testing of other family members. DNA analysis of the patient revealed R218H, a mutation in the serum albumin gene associated with FDH, which was also present in the patient's euthyroid father and brother. Thyroid scans, serum thyroglobulin measurements, and free T4 measurements using equilibrium dialysis or 2-step immunoassay methods can identify thyroid hormone-binding protein defects and simplify the diagnosis and treatment of infants with CH.

Albumins↗
PubMed2003

Structural basis of albumin-thyroxine interactions and familial dysalbuminemic hyperthyroxinemia.

Human serum albumin (HSA) is the major protein component of blood plasma and serves as a transporter for thyroxine and other hydrophobic compounds such as fatty acids and bilirubin. We report here a structural characterization of HSA-thyroxine interactions. Using crystallographic analyses we have identified four binding sites for thyroxine on HSA distributed in subdomains IIA, IIIA, and IIIB. Mutation of residue R218 within subdomain IIA greatly enhances the affinity for thyroxine and causes the elevated serum thyroxine levels associated with familial dysalbuminemic hyperthyroxinemia (FDH). Structural analysis of two FDH mutants of HSA (R218H and R218P) shows that this effect arises because substitution of R218, which contacts the hormone bound in subdomain IIA, produces localized conformational changes to relax steric restrictions on thyroxine binding at this site. We have also found that, although fatty acid binding competes with thyroxine at all four sites, it induces conformational changes that create a fifth hormone-binding site in the cleft between domains I and III, at least 9 A from R218. These structural observations are consistent with binding data showing that HSA retains a high-affinity site for thyroxine in the presence of excess fatty acid that is insensitive to FDH mutations.

Albumins↗
PubMed1996

Mutations in a specific human serum albumin thyroxine binding site define the structural basis of familial dysalbuminemic hyperthyroxinemia.

The familial dysalbuminemic hyperthyroxinemia (FDH) phenotype results from a natural human serum albumin (HSA) mutant with histidine instead of arginine at amino acid position 218. This mutation results in an enhanced affinity for thyroxine. Site-directed mutagenesis and a yeast protein expression system were used to synthesize wild type HSA and FDH HSA as well as several other HSA mutants. Studies on the binding of thyroxine to these HSA species using equilibrium dialysis and quenching of tryptophan 214 fluorescence suggest that the FDH mutation affects a single thyroxine binding site located in the 2A subdomain of HSA. Site-directed mutagenesis of HSA and thyroxine analogs were used to obtain information about the mechanism of thyroxine binding to both wild type and FDH HSA. These studies suggest that the guanidino group of arginine at amino acid position 218 in wild type HSA is involved in an unfavorable binding interaction with the amino group of thyroxine, whereas histidine at amino acid position 218 in FDH HSA is involved in a favorable binding interaction with thyroxine. Neither arginine at amino acid position 222 nor tryptophan at amino acid position 214 appears to favorably influence the binding of thyroxine to wild type HSA.

Binding Sites↗
PubMed2004

Artifactually elevated serum-free thyroxine levels measured by equilibrium dialysis in a pregnant woman with familial dysalbuminemic hyperthyroxinemia.

Familial dysalbuminemic hyperthyroxinemia (FDH) is a familial autosomal dominant syndrome caused by abnormal albumin with an increased affinity for thyroxine (T4). Two types of mutations in the albumin gene, replacing the normal arginine 218 with a histidine (R218H) or a proline (R218P), have been reported to cause FDH. Here, we report a pregnant Japanese woman with FDH caused by the mutant albumin R218P. She had extremely elevated total T4 levels but normal TSH. While the majority of T4was bound to albumin, T4 binding to thyroxine-binding globulin (TBG) was progressively increased throughout pregnancy. Her infant also had elevated serum T4 but normal thyrotropin (TSH). The presence of a guanine to cytosine transition in the second nucleotide of codon 218 of the albumin gene, resulting in a substitution of proline for the normal arginine (R218P), was revealed in the proband. Serum free thyroxine (FT4) levels were increased when measured with some commercial kits including equilibrium dialysis followed by radioimmunoassay (RIA) but not when determined by RIA after ultrafiltration of sera. These results indicate an increased T4 binding to TBG during pregnancy in the patients with FDH. Furthermore, our results suggest that normal serum FT4 determined by equilibrium dialysis is not an ultimate standard for the diagnosis of FDH in the patients with the mutant albumin R218P.

Adult↗
PubMed1993

Thyroid scintigraphy of hyperthyroxinemia.

The term "hyperthyroxinemia" encompasses clinical syndromes associated with elevated levels of thyroid hormone in the presence of increased, normal, or decreased thyroid function. The clinical presentation (i.e., history and physical examination), in vitro thyroid function tests, as well as radioisotope thyroid imaging all play key roles in the diagnosis of the underlying thyroid disorder. Many of these disorders and their appearance on thyroid scintigraphy are presented in this atlas.

Adult↗
PubMed1995

Hyperthyroxinemia and elevated lipids as paraneoplastic phenomena in hepatocellular carcinoma. A case report.

In the United States and Western Europe, primary hepato-cellular carcinoma is an uncommon malignancy. Even though many well-defined associations have been reported, paraneoplastic manifestations are rare in North American patients. We describe an adolescent with complaints of weight loss, weakness, and a sensation of ¿fullness in the upper abdomen.¿ On initial laboratory workup a lactescent serum was found, with the following abnormalities; serum cholesterol level of 573 mg/dl (normal 120-260), triglycerides of 1,761 mg/dl (normal 10-190), and serum thyroxine level of 21 microgram/dl (normal 5.5-12.3). Serum albumin, calcium, and thyroid-stimulating hormone levels were also minimally elevated. Liver biopsy confirmed hepatocellular carcinoma. This is a rare hepatoma, which in our case manifested with multiple paraneoplastic phenomena, including hyperthyroxinemia, hypercholesterolemia, hypertriglyceridemia, and hyperalbuminemia. We review the pertinent literature.

Adolescent↗
PubMed1993

Fluorescence investigations of albumin from patients with familial dysalbuminemic hyperthyroxinemia.

Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant syndrome in which clinically euthyroid patients have elevated total thyroxine levels. These high serum thyroxine levels are traceable to altered binding of thyroxine to the patient's albumin. Albumin from FDH patients and normal volunteers have been purified. Reverse-phase and ion-exchange high performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis on the FDH-human serum albumin (HSA) samples show a single band that comigrates with normal HSA. In both protein solutions the intrinsic fluorescence, upon 280 nm excitation, is predominantly due to the single tryptophan residue. The quantum yield of this intrinsic fluorescence in the FDH-HSA solutions is, however, reduced relative to that of HSA. Furthermore, the "average" lifetime value of the tryptophan emission in the FDH-HSA sample is less than that of normal HSA, consistent with its reduced quantum yield. The binding of thyroxine to both albumins effectively quenches the tryptophan emission probably via a nonradiative energy transfer mechanism. Time-resolved data suggest that the albumin from the dysalbuminemic patients is actually an approximately equimolar mixture of normal HSA and FDH-HSA indicative of heterologous expression. Quenching of the intrinsic HSA and FDH-HSA fluorescence by serial additions of thyroxine showed enhanced quenching of FDH-HSA relative to HSA at any T4 to albumin mole ratio, therefore supporting earlier reports of increased thyroxine affinity to FDH-HSA.

Genetic Variation↗
PubMed1996

Familial dysalbuminemic hyperthyroxinemia and thyroid hormone autoantibodies: interference in current free thyroid hormone assays.

The interference of familial dysalbuminemic hyperthyroxinemia (FDH), antithyroxine (anti-T4) or antitriiodothyronine (anti-T3) antibodies in serum free T4 (FT4) or free T3 (FT3) assays depends on the assay method: two-step immunoextraction, one-step labelled ligand (analogue or derivative tracer) or labelled antibody (solid-phase antigen-linked technique: SPALT) method. For FDH subjects, only FT4 measurements by one two-step method gave reliable results in all cases. However, the overestimation was less marked with new SPALT assays than with previous analogue-based assays. In sera containing anti-T4 antibodies, two-step assays and SPALT assays with a T3-coated solid phase can be considered as reliable for FT4 determination. All other methods including SPALT assays with a T4-coated solid phase may give falsely high results. In sera containing anti-T3 antibodies, SPALT FT4 and FT3 assays with a T3-coated solid phase may give spuriously high values. Anti-T3 antibodies do not interfere in two-step FT3 assays and SPALT FT3 assays with a T2-coated solid phase, but may give high FT3 values as measured by analogue or derivative methods. Moreover, SPALT free thyroid hormone assays may also be subject to interference from antibodies directed towards the assay solid phase.

Autoantibodies↗
PubMed1987

Role of serum carrier proteins in the peripheral metabolism and tissue distribution of thyroid hormones in familial dysalbuminemic hyperthyroxinemia and congenital elevation of thyroxine-binding globulin.

To investigate the role of thyroxine-binding globulin (TBG) and albumin in the availability of thyroid hormones to peripheral tissues, comprehensive kinetic studies of thyroxine (T4) and triiodothyronine (T3) were carried out in eight subjects with familial dysalbuminemic hyperthyroxinemia (FDH), in four subjects with inherited TBG excess, and in 15 normals. In high-TBG subjects, the reduction of T4 and T3 plasma clearance rates (by 51% and 54%, respectively) was associated with normal daily productions; T4 and T3 distribution volumes were significantly reduced. In FDH subjects T4 clearance was less reduced (by 31%) than in high TBG; consequently T4 production rate was significantly increased (by 42%); T4 and T3 distribution volumes and T3 clearance rate were unchanged. Increased T3 peripheral production in FDH (by 24%) indicates that T4 bound to abnormal albumin is more available to tissues than T4 carried by TBG, thus suggesting an important role of albumin in T4 availability to the periphery.

Adult↗
PubMed1995

Thyrotropin receptor-specific antibodies in BALB/cJ mice with experimental hyperthyroxinemia show a restricted binding specificity and belong to the immunoglobulin G1 subclass.

Immunization with the extracellular domain of TSH receptor (TSHR) led to the development of hyperthyroxinemia in BALB/cJ, but not C57BL/6J, SJL/J, and B10.BR, mice. Earlier, human studies had shown that thyroid-stimulating antibodies are predominantly of the immunoglobulin G1 (IgG1) subclass with a narrow specificity to TSHR, and antibodies that block thyroid function could be of any subclass with a broader specificity. Therefore, antibody responses in susceptible (BALB/cJ) and resistant (SJL/J) mice were characterized. There were no significant differences in the titers, relative affinities, or isotypes of antibodies against the TSHR. BALB/cJ and SJL/J sera reacted with 2 and 7 of 26 overlapping peptides from the extracellular domain of the TSHR. The ability of sera from BALB/cJ and SJL/J mice to block TSH binding to TSHR was reversed by 1 and 6 of the reactive peptides, respectively. BALB/cJ mice showed predominantly an IgG1 response against the TSHR and peptides, whereas SJL/J mice showed varying levels of all IgG subclasses. Although SJL/J sera reacted with peptides to which blocking antibodies bind, they did not show hypothyroidism, suggesting that their sera contained a mixture of blocking and stimulating antibodies that negated the effects of each other. In contrast, some TSHR-specific antibodies in BALB/cJ probably represented stimulating antibodies.

Animals↗
PubMed1988

Normal cellular uptake of thyroxine from serum of patients with familial dysalbuminemic hyperthyroxinemia or elevated thyroxine-binding globulin.

To determine whether thyroid hormone-binding proteins in serum, particularly albumin, facilitate the transfer of T4 into human tissues, we studied cellular T4 uptake (CT4) by human liver (Hep G2) cells from medium containing serum from subjects with familial dysalbuminemic hyperthyroxinemia (FDH) and acquired and familial T4-binding globulin (TBG) excess and patients with normal T4-binding to albumin and normal TBG concentrations. Serum from nine subjects with FDH whose mean serum total T4 (TT4) concentration was 203 +/- 27 nmol/L were matched for TT4 concentrations with serum from nine subjects with acquired TBG excess (TT4, 201 +/- 23 nmol/L) and nine subjects with thyrotoxicosis and normal TBG concentrations (TT4, 205 +/- 28 nmol/L). The subjects' CT4 results were compared to their serum free T4 concentration, measured by equilibrium dialysis (DT4), and their serum free T4 index (FT4I) value. The mean serum DT4 value for the subjects with FDH (23 +/- 5 fmol/L) and those with TBG excess (23 +/- 3 fmol/L) were normal, whereas it was elevated (44 +/- 9 fmol/L; P less than 0.001) for the thyrotoxic patients with normal TBG concentrations. The mean CT4 value also was normal for the subjects with FDH (37.7 +/- 4.9 fmol/plate) and those with TBG excess (36.6 +/- 4.6 fmol/plate), but was elevated for the thyrotoxic patients (62.3 +/- 11.2 fmol/plate; P less than 0.001). In all three groups studied, the relationship between individual CT4 and DT4 values was similar to that previously found in subjects with no T4-binding protein abnormalities. The mean serum FT4I value was lower for the subjects with acquired TBG excess (111 +/- 22) than for the subjects with FDH (133 +/- 22; P less than 0.05), and it was much higher for the subjects with thyrotoxicosis (221 +/- 31; P less than 0.001). In the subjects with FDH and those with thyrotoxicosis the normal relationship between CT4 and FT4I was maintained, while in the subjects with acquired TBG excess, FT4I values were lower than expected. In seven of the nine subjects with TBG excess, the abnormality was associated with conditions known to increase its sialic acid content: hepatitis (one subject), pregnancy (four subjects), and estrogen therapy (two subjects). The CT4 values were similar in nine subjects with acquired TBG excess (seven pregnant women and two subjects with chronic active hepatitis) and five subjects with familial TBG excess (34.8 +/- 4.3 vs. 34.0 +/- 8.6 fmol/plate, respectively).(ABSTRACT TRUNCATED AT 400 WORDS)

Cell Line↗
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↗
PubMed1994

Postpartum thyroiditis and familial dysalbuminemic hyperthyroxinemia.

Familial dysalbuminemic hyperthyroxinemia (FDH) is a syndrome associated with euthyroidism and increased binding of T4 to serum albumin. The combined occurrence of FDH and postpartum hyperthyroidism due to Graves' disease has only been reported in one patient. We now describe the first case of FDH and thyrotoxicosis due to postpartum silent thyroiditis. In a 19-yr-old woman, FDH, suspected on the basis of strikingly elevated analog free T4 (fT4) and total T4 values, but normal two-step fT4 and serum TSH values, was confirmed by [125I]T4 agarose-gel electrophoresis. When FDH and thyrotoxicosis, characterized by markedly elevated analog fT4, total T4, and two-step fT4 values and undetectable TSH values, coexist, the differential diagnosis may be confusing.

Adult↗
PubMed2000

Familial dysalbuminemic hyperthyroxinemia in a Swiss family caused by a mutant albumin (R218P) shows an apparent discrepancy between serum concentration and affinity for thyroxine.

Familial dysalbuminemic hyperthyroxinemia (FDH), is the most common cause of inherited increase in serum total T4 (TT4) in the Caucasian population. It is caused by a mutation (R218H) in the human serum albumin (HSA) gene, resulting in 10-fold higher affinity for T4 and, in heterozygous affected subjects, a TT4 level 2-fold higher than that in subjects expressing the wild-type HSA only. We now report FDH in a Swiss family, caused by HSA R218P, previously reported in subjects of Japanese origin. In this form of FDH, serum TT4 levels are 14- to 20-fold the normal mean, confirmed by measurements in serum extracts. TrT3 and TT3, concentrations are 7- and 2-fold above the mean, respectively. Thus, to maintain a normal free T4 level, the calculated affinity constant (Ka) of HSA R218P should be about 16-fold higher than that of HSA R218H. Surprisingly, the Ka values measured at saturation were similar: 5.4 x 10(6) and 6.4 x 10(6) mol/L(-1) for HSA R218H, respectively. To determine how subjects with HSA R218P and R218P maintain a euthyroid state despite the markedly high serum TT4, the concentration of dialyzable T4 was measured at increasing amounts of TT4. At a TT4 level equivalent to that found in the subjects with HSA R218P, the absolute FT4 concentrations were 40, 432, and 1970 pmol/L for sera expressing HSAs R218P, R218H, and wild type, respectively. Thus, the affinity of HSA R218P for T4 must be higher than that of R218H to produce an 11-fold difference in FT4 at the same concentration ofTT4 This difference was obliterated at saturating concentrations of TT4 used for the determination of Ka values by the method of Scatchard.

Amino Acid Substitution↗
PubMed1990

Can the type of variant albumin in familial dysalbuminemic hyperthyroxinemia be determined by measuring iodothyronines in serum?

A recent report documented the existence of three putative types of variant albumin in dysalbuminemic hyperthyroxinemia (DH) and suggested that measurement of the total concentration of three iodothyronines (T4, T3 and rT3) in serum of affected subjects could aid in their differentiation. In the present report, we describe three affected subjects from a single family which DH exhibited, in addition to increased serum total T4 levels, variable changes in the concentrations of total T3 and rT3. The concentrations of the following iodothyronines were above the normal limit: T4, T3 and rT3 in the propositus, T4 and T3 but not rT3 in her sister, and T4 but not T3 and rT3 in her mother. These differences cannot be caused by structurally different types of variant albumins, because the three subjects are members of the same family. They rather correlated with the relative abundance of the variant albumin in serum of the affected family members. Although previously reported subjects with DH always had serum T4 levels above the normal limit due to the predominantly higher affinity of the variant albumin for T4, significant increases in the concentration of serum T3 and rT3, reaching at times values above the upper normal range, have also been observed. Since a number of factors, including the relative abundance of the variant albumin, influence the concentration of iodothyronines in serum, their measurement alone cannot be used to determine the inherited type of DH.

Adult↗
PubMed1989

Hyperprealbuminemia, euthyroid hyperthyroxinemia, Zollinger-Ellison-like syndrome and hypercorticism in a pancreatic endocrine tumour.

Prealbumin, one of the main thyroxine transport proteins, has recently been shown to be a valuable immunohistochemical marker of neuroendocrine tumours. We report the case of a multisecretory pancreatic endocrine tumour whose prealbumin secretion was so high that it produced a peak on routine serum protein electrophoresis and induced a euthyroid hyperthyroxinemia. The maximal binding capacity of prealbumin for thyroxine was indeed markedly increased, whereas its affinity for this hormone was normal. The tumour was associated with gastric hyperacidity and hypergastrinemia thereby evoking a Zollinger-Ellison syndrome. The secretin stimulation test and gastrin tumoural immunohistochemistry were, however, negative. We suggest that the concomitant tumoural production of gastrin-releasing peptide was responsible for the gastric hyperacidity and hypergastrinemia. This hormone probably also accounted for a moderate hypercorticism.

Adrenocortical Hyperfunction↗