Heterogeneity of Thyroxine Binding by Serum Albumins in Normal Subjects and Patients with Familial Dysalbuminemic Hyperthyroxinemia*

Yabu, Yukiko; Amir, Syed M.; Ruiz, Mercedes; Braverman, Lewis E.; Ingbar, Sidney H.

doi:10.1210/jcem-60-3-451

Cited by 33 publications

(4 citation statements)

References 13 publications

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“…The total tri-iodothyronine (T 3 ) (tT 3 ) and thyroidstimulating hormone (TSH) concentrations, usually, are normal (1)(2)(3)(4)(5)(6). These discrepancies are due to the presence of an abnormal serum albumin that exhibits enhanced binding of T 4 , and patients with FDH are clinically euthyroid (7)(8)(9)(10). Although FDH has been widely reported in the medical literature and accounts for the most common cause of genetic euthyroid hyperthyroxinemia in western countries, particularly among hispanics of Puerto Rican origin (11)(12)(13), to our knowledge no case has been reported in individuals of Chinese or African origin.…”

Section: Introductionmentioning

confidence: 99%

A point mutation in the albumin gene in a Chinese patient with familial dysalbuminemic hyperthyroxinemia

Tang

Yang²,

Choo³

et al. 1999

European Journal of Endocrinology

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Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant disorder characterized by euthyroid hyperthyroxinemia. However, FDH has not been reported in Chinese or African patients. Here, we report the first case of FDH in a Chinese patient. A 69-year-old Chinese man was found to have increased serum total T 4 concentrations (198-242 nmol/l; normal range 58-148 nmol/l) and free T 4 concentrations (>58 pmol/l; T 4 analog method, normal range 9-28 pmol/l). Serum total T 3 and TSH concentrations were normal. The patient was misdiagnosed as hyperthyroid and was later suspected to have a TSH-producing tumor by the finding of a pituitary microadenoma, which was eventually proven to be a non-functional pituitary 'incidentaloma'. Electrophoretic analysis of the patient's serum proteins demonstrated enhanced albumin binding of [ 125 I]T 4 . Serum free T 4 concentrations were normal (16-19 pmol/l, normal range 9-26 pmol/l) when a two-step method was used. Direct sequencing of the albumin gene showed a guanine to adenosine transition in the second nucleotide of codon 218, resulting in a substitution of histidine (CAC) for the normal arginine (CGC) in one of the two alleles in the patient. The point mutation was further confirmed by HphI digestion of exon 7 of the albumin gene. The patient's son was not affected. Our studies demonstrated that the point mutation of the albumin gene in a Chinese patient with FDH was similar to that found in western white families, but differed from that in a Japanese family in whom a guanine to cytosine transition at the same position was found.

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Section: Introductionmentioning

confidence: 99%

A point mutation in the albumin gene in a Chinese patient with familial dysalbuminemic hyperthyroxinemia

Tang

Yang²,

Choo³

et al. 1999

European Journal of Endocrinology

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“…8 (17)(18)(19). The molecular basis of the increased affinity of albumin for T4 is unresolved (20). Increased binding of T4 to IgG most often is seen in the setting of autoimmune thyroid disease such as Hashimoto's thyroiditis (21).…”

Section: Methodsmentioning

confidence: 99%

A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia.

et al. 1990

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In a family expressing euthyroid hyperthyroxinemia, an increased association of plasma thyroxine (T4) with transthyretin (TTR) is transmitted by autosomal dominant inheritance and is secondary to a mutant TTR molecule with increased affinity for T4. Eight individuals spanning three generations exhibited the abnormality. Although five of eight individuals had elevated total T4 concentrations, all affected individuals were clinically euthyroid and all had normal free T4 levels. Purified TIR from the propositus had an affinity for 125I-T4 three times that of control 1TTR. Exons 2, 3, and 4 (representing > 97% of the coding sequence) of the TIR gene of DNA prepared from the propositus' peripheral blood leukocytes were amplified using the polymerase chain reaction (PCR) and were sequenced after subcloning. Exons 2 and 3 were indistinguishable from normal. In 50% of clones amplified from exon 4, a substitution of adenine (ACC) for guanine (GCC) in codon 109 resulted in the replacement of threonine-for-alanine, a mutation confirmed by amino acid sequencing of tryptic peptides derived from purified plasma TTR. The adenine-for-guanine substitution abolishes one of two Fnu 4H I restriction sites in exon 4. PCR amplification of exon 4 of TT7R and restriction digestion with Fnu 4H I confirmed that five affected family members with increased binding of 25.I-T4 to TMR are heterozygous for the threonine 109 substitution that increases the affinity of this abnormal TIR for T4. (J. Clin.

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“…Isoelectric focusing has shown that in normal albumin, radioiodinated T4 mostly binds to two bands with pi 5.44 and 5.31 and, to a much lesser extent, to two additional bands (pi 5.22 and 4,97) (35). In FDH albumin, however, most T4 is bound to the latter bands (35).…”

Section: As Shown Inmentioning

confidence: 99%

“…In FDH albumin, however, most T4 is bound to the latter bands (35). It has been suggested that the increased affinity and specificity of the variant albumin for thyroid hormone might reside in the formation of an electrostatic bond between the ionized phenolic hydroxyl of the iodothyronine and a cationic group on the protein (36).…”

Section: As Shown Inmentioning

confidence: 99%

Variations in Thyroid Hormone Transport Proteins and Their Clinical Implications

Bartalena¹,

Robbins²

1992

Thyroid

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Variations in major thyroid hormone transport proteins may be inherited or acquired and may be associated with changes in serum concentration of the proteins or their affinity for thyroid hormones. These variations most frequently involve thyroxine-binding globulin (TBG), but changes in transthyretin and albumin are also observed. The consequent alteration of thyroid hormone-binding capacity in serum is associated with variations in total thyroid hormone concentration. Increased serum total thyroid hormone levels are found in subjects with TBG excess, familial dysalbuminemic hyperthyroxinemia, and transthyretin-associated hyperthyroxinemia. Conversely, diminished serum thyroid hormone values are observed in subjects with TBG deficiency, and decreased concentration or affinity of transthyretin and albumin is not associated with variations in serum concentrations of thyroid hormones. The transport protein-associated variations in serum total thyroid hormone concentrations do not reflect a change in thyroid status. Euthyroidism can be easily established in subjects with transport protein abnormalities by the normal free thyroid hormone and TSH concentrations. It is, however, crucial to select methods for free thyroid hormone measurement that are not affected by abnormalities of transport proteins. Some assays, such as the analog method, often provide artifactual and misleading results, which may lead to inappropriate and even detrimental treatments. The evolutionary advantage of TBG (and albumin) in terms of thyroid homeostasis still remains to be elucidated.

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Heterogeneity of Thyroxine Binding by Serum Albumins in Normal Subjects and Patients with Familial Dysalbuminemic Hyperthyroxinemia*

Cited by 33 publications

References 13 publications

A point mutation in the albumin gene in a Chinese patient with familial dysalbuminemic hyperthyroxinemia

A point mutation in the albumin gene in a Chinese patient with familial dysalbuminemic hyperthyroxinemia

A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia.

Variations in Thyroid Hormone Transport Proteins and Their Clinical Implications

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