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PubMed1997

A novel missense mutation in codon 218 of the albumin gene in a distinct phenotype of familial dysalbuminemic hyperthyroxinemia in a Japanese kindred.

Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasians. To our knowledge, no such documentation on Asians exists. Six of 8 members of a 3-generation Japanese family were found by us to carry the FDH phenotype. Serum total T4 levels ranged from 1763.2-2741.3 nmol/L (normal range, 65.6-164.7), serum total T3 levels ranged from 2.73-5.62 nmol/L (normal range, 1.47-2.95), and rT3 levels ranged from 1.08-2.52 nmol/L (normal range, 0.22-0.60). In the proband, the majority of [125I]T4 in serum T4-binding proteins was distributed in albumin fractions, and the isolated albumin had an increased affinity for T4. A guanine to cytosine transition in the second nucleotide of codon 218, resulting in replacement of normal arginine with proline, was detected in 1 of 2 alleles in all 5 subjects of the family with FDH. In all FDH-affected Caucasian subjects from 10 unrelated families with a moderate increase in serum T4, the guanine to adenine transition was demonstrated at the same position of the albumin gene as noted in our patients, but histidine, the replacement amino acid, differed from proline noted in our FDH Japanese subjects. It would thus appear that FDH has ethnic variations.

Adult↗
PubMed1999

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

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 (198-242nmol/l; normal range 58-148nmol/l) and free T(4) concentrations (>58pmol/l; T(4) analog method, normal range 9-28pmol/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 (16-19pmol/l, normal range 9-26pmol/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.

Aged↗
PubMed1990

Transient prealbumin-associated hyperthyroxinemia in TSH-producing pituitary adenoma.

This case report describes a 38-year-old male who was hospitalized for further clarification of clinically mild hyperthyroidism. His increased total hormone levels, the elevated free thyroid hormones and the elevated basal TSH with blunted response to TRH strongly suggested a pituitary adenoma with inappropriate TSH incretion. Transmission computed tomography showed an intrasellar expansion, 16 mm in diameter. The neoplastic TSH production was confirmed by an elevated alpha-subunit and a raised molar alpha-sub/TSH ratio. However, T4 distribution on prealbumin (PA, TTR), albumin (A) and thyroxine binding globulin (TBG) showed a clearly increased binding to PA (39%), indicating additional prealbumin-associated hyperthyroxinemia. The absolute values of PA, A and TBG were within the normal range. After removal of the TSH-producing adenoma, basal TSH, the free thyroid hormones and T4 binding to prealbumin returned to normal. Therefore, the prealbumin-associated hyperthyroxinemia had to be interpreted as a transitory phenomenon related to secondary hyperthyroidism (T4 shift from thyroxine binding globulin to prealbumin) rather than a genetically conditioned anomaly of protein binding.

Adenoma↗
PubMed1989

Hyperthyroxinemia in patients receiving thyroid replacement therapy.

Eleven patients, with a history of hypothyroidism, who had hyperthyroxinemia and an elevated free thyroxine index but normal serum triiodothyronine concentrations on levothyroxine replacement underwent levothyroxine dose reduction at three-month intervals until the free thyroxine index fell into the normal range. All were clinically euthyroid throughout. Normalization of the thyrotropin response to thyrotropin-releasing hormone occurred concomitantly, indicating correction of subtle hyperthyroidism. The mean thyroxine dose decreased from 161 micrograms/d (2.06 micrograms/kg) to 120 micrograms/d (1.51 micrograms/kg). The resting heart rate fell in eight of 11 patients (P less than .02). The left ventricular ejection fraction decreased in eight of 11 patients, although the decrease was not statistically significant. Considering the sensitivity of pituitary, cardiac, and bone tissue to even a small excess of thyroxine over time, hyperthyroxinemia associated with an elevated free thyroxine index should be corrected even in patients taking levothyroxine replacement who are clinically euthyroid and whose serum triiodothyronine concentrations are within normal limits.

Adult↗
PubMed1988

Detection of protein binding abnormalities in euthyroid hyperthyroxinemia.

This is a procedure for rapidly identifying the three common abnormalities in binding of thyroxin by protein. After incubation with [125I]thyroxin, serum proteins are separated by electrophoresis on agarose gel and binding of thyroxin to the various protein fractions is determined after autoradiography. Quantitatively abnormal binding to albumin or prealbumin and thyroxin autoantibodies is easily demonstrated by this technique. Normally, less than 6% is bound to albumin, and no binding by prealbumin is detected. In dysalbuminemic hyperthyroxinemia, about 30% of the serum thyroxin is bound to albumin; in prealbumin-associated hyperthyroxinemia, 7% is bound to prealbumin. With this procedure these protein-binding abnormalities can be simply identified, and it may be useful when results of a thyroxin assay are not consistent with results of a sensitive thyrotropin assay or the patient's clinical examination.

Autoantibodies↗
PubMed1994

[Familial dysalbuminemic hyperthyroxinemia in long-term amiodarone treated patients].

A serum sample of an outpatient, under long-term amiodarone (AM) treatment was submitted for routine checkup of thyroid function parameters. It revealed the pattern of euthyroid dysalbuminemic hyperthyroxinemia. Since no results have been published so far covering the influence of amiodarone on the specific thyroxine binding proteins, we undertook a prospective study to investigate 28 amiodarone patients, comparing these with a series of age and sex matched euthyroid subjects. Not one amiodarone patient showed changed radio-T4 distribution against the normal group. Yet, in 3 relatives of the propositus, familial screening revealed the typical pattern of thyroid function tests and of T4 distribution in radio immune ice gel electrophoresis, respectively, proving familial dysalbuminemic hyperthyroxinemia syndrome. Thus, it is most likely that this syndrome has been prevalent already prior to the amiodarone administration and consequently amiodarone was of no influence on thyroxine transport protein patterns.

Adult↗
PubMed1994

[Thyroxine-binding proteins--familial euthyroid hyperthyroxinemia due to point mutations of transthyretin].

Some of the point mutations in transthyretin (TTR) exhibit increased affinity for thyroxine (T4) and result in euthyroid hyperthyroxinemia in affected individuals. TTR, also known as thyroxine binding prealbumin, is a homotetrameric plasma protein of MW 55,000 that transports 15% of serum T4. The known point mutations that cause euthyroid hyperthyroxinemia are Ala109 (ACC) to Thr (GCC) and Gly6 (GGT) to Ser (AGT). These mutations are transmitted by autosomal dominant inheritance. The laboratory findings are an elevated total T4, an increased free T4 index, a normal free T4, and normal levels of total and free triiodothyronine. The Thr109 mutation abolishes Fnu4HI restriction site, and the Ser6 mutation eliminates the Msp I restriction site.

Diagnosis, Differential↗
PubMed1987

Thyrotropin hyperresponsiveness to TRH despite hyperthyroxinemia in amiodarone-treated subjects.

Pituitary responsiveness to TRH was assessed prospectively over 24 weeks, in 15 patients receiving 300 mg amiodarone a day. All developed significant hyperthyroxinemia (both total and free), and marked elevations in reverse T3 compared to pretreatment levels. Although basal TSH levels were unchanged in all of them, TSH increased by greater than 50% when compared to pretreatment responses, in eight patients, while they remained unchanged (+/- 15%) in the remaining seven. All eight with exaggerated responses also showed significant reductions (P less than .001) in plasma levels of total and free T3, whereas in the seven who did not show any increase in TSH responses, T3 levels were unchanged. The increase in TSH response to TRH was strongly correlated (r = -.82, P less than .001) with T3 levels. Total and free T4 levels were equally elevated in both groups. These observations indicate that amiodarone effectively blocks the suppressive effect of hyperthyroxinemia on TSH secretion, and that T3 is the mediator of thyroid feedback control in amiodarone treated patients.

Amiodarone↗
PubMed1985

Familial euthyroid hyperthyroxinemia secondary to pituitary and peripheral resistance to thyroid hormones.

Among 18 family members, representing four generations studied, a familial form of euthyroid hyperthyroxinemia was found in 6. The increased serum total thyroxine value in all hyperthyroxinemic subjects could not be explained by abnormalities in binding proteins. Five of the six patients had a goiter, and all had increased concentrations of triiodothyronine and free thyroxine without symptoms or signs of hyperthyroidism. Basal serum levels of thyroid-stimulating hormone (thyrotropin) were normal in all six; in the four who were tested, these levels responded normally to thyrotropin-releasing hormone (TRH). The normal suppression of basal and TRH-stimulated thyrotropin increase after administration of triiodothyronine did not occur. These patients seem to have resistance of peripheral and pituitary tissues to the actions of thyroid hormones. Family studies revealed that the disorder appeared as a new sporadic mutation and was consistent with an autosomal-dominant mode of inheritance. This disorder, an important example of euthyroid hyperthyroxinemia, should not be confused with Graves' disease.

Adolescent↗
PubMed1985

Euthyroid hyperthyroxinemia and rapid cycling affective disorder: case report.

A 32-year-old woman with rapid cycling bipolar illness had numerous clinical problems throughout 19 affective episodes and six hospital admissions within 34 months. Persistent hyperthyroxinemia, always associated with manic episodes, led to a diagnostic work-up that ruled out a primary thyroid dysfunction and pointed to oral contraceptives, appetite suppressants, and psychiatric illness as likely causes of elevated T4 values. The contention that an underlying thyroid hypofunction is the basis of rapid cycling is questioned. The extent to which a bipolar disorder increases T4 levels and the role of euthyroid hyperthyroxinemia in the pathogenesis of rapid cycling are discussed.

Adult↗
PubMed1983

Propranolol-induced hyperthyroxinemia.

A patient on a regimen of 400 mg/day of propranolol hydrochloride was observed to have elevated thyroxine (T4) and free T4 levels with a normal thyrotropin response to protirelin. This led us to study the prevalence of hyperthyroxinemia in 14 consecutively treated patients with hypertension on daily doses of propranolol of 320 mg or more. Four of 14 patients had elevated serum T4 levels. As a group, the patients on propranolol therapy had higher serum T4 levels, free T4 indices, and triiodothyronine levels than did healthy controls. The use of high-dosage propranolol may be associated with euthyroid hyperthyroxinemia and be a source of diagnostic confusion. All patients receiving therapy with high-dosage propranolol should undergo protirelin testing before one can conclude that their elevated thyroid hormone levels are due to hyperthyroidism.

Humans↗
PubMed2001

Transthyretin mutations in hyperthyroxinemia and amyloid diseases.

Over 80 different disease-causing mutations in transthyretin (TTR) have been reported. The vast majority are inherited in an autosomal dominant manner and are related to amyloid deposition, affecting predominantly peripheral nerve and/or the heart. A small portion of TTR mutations are apparently non-amyloidogenic. Among these are mutations responsible for hyperthyroxinemia, presenting high affinity for thyroxine (a TTR ligand). Compound heterozygotic individuals for TTR mutants have been described; noteworthy is the clinically protective effect exerted by a non-pathogenic over a pathogenic mutation. Current TTR mutations and their significance are briefly reviewed here.

Amyloid↗
PubMed1994

An identical missense mutation in the albumin gene results in familial dysalbuminemic hyperthyroxinemia in 8 unrelated families.

Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common form of inherited increase of serum thyroxine in Caucasians. It is the result of increased thyroxine-binding to serum proteins and is inherited as a dominant trait. The entire coding region of the albumin gene of a subject with FDH was sequenced. A single nucleotide substitution, G to A transition in codon 218, was found in one of the two alleles, resulting in the replacement of the normal Arg with His. This mutation was found in 9 affected family members but not in 8 unaffected relatives and 18 unrelated normal individuals. The same missense mutation was found in 12 other subjects with FDH belonging to 7 unrelated families. In every individual with FDH, the mutation was associated with the Sac I+ polymorphism in the albumin gene, strongly suggesting a founder effect.

Arginine↗
PubMed1987

A four generation study of familial dysalbuminemic hyperthyroxinemia: diagnosis in the presence of an acquired excess of thyroxine-binding globulin.

We have studied the largest kindred with familial dysalbuminemic hyperthyroxinemia (FDH) thus far reported, comprising thirty-three blood relations in four generations and three of their spouses. Our objective was to complement previous evidence concerning the precise mode of inheritance of FDH and to detect any other features of the disorder that had not yet been noted. Among the thirty three, there were thirteen patients with FDH, eight males and five females, in all of whom the abnormality appeared to be fully expressed. Within the kindred, no affected female has borne a female child, but transmission from female to male, male to male, and male to female has been observed. Among the offspring of individuals with FDH, the overall observed frequency of FDH in three filial generations was 12/22, or 54.5 per cent, yielding a computed penetrance ratio of 1.09. Four of the patients with FDH had been investigated for hyperthyroidism, and two of them had mistakenly been treated. Of particular interest were two women with FDH who were receiving oral contraceptives and whose serum thyroxine-binding globulin (TBG) concentrations were increased. The results of their thyroid function tests differed from those of patients with FDH whose TBG concentrations were normal and mainly suggested the presence of only a high TBG state. The diagnosis of FDH in these two patients was obscured, and probably would not have been made were it not for the present investigation, which led to the electrophoretic demonstration of increased binding of T4 by serum albumin.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
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↗