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PubMed1982

Familial dysalbuminemic hyperthyroxinemia: a syndrome that can be confused with thyrotoxicosis.

We investigated 15 euthyroid patients from eight families with a recently recognized syndrome, familial dysalbuminemic hyperthyroxinemia (FDH), that could be mistaken for thyrotoxicosis. The syndrome is characterized by elevations in serum thyroxine and the free-thyroxine index (FT4l), which are due to an abnormal serum albumin that preferentially binds thyroxine. This albumin has an abnormal binding site with a much greater affinity for thyroxine (relative to its affinity for triiodothyronine) than that of the hormone-binding site on thyroxine-binding globulin. Results of thyrotropin-releasing hormone and thyroid-suppression tests, as well as direct measurements of the free-thyroxine concentration by equilibrium dialysis, are normal in these patients, although the serum triiodothyronine concentration may be slightly elevated. Although its prevalence is uncertain, FDH may be more common than suspected; we have seen 26 cases within the past year.

Adolescent↗
PubMed1990

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

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 TTR from the propositus had an affinity for 125I-T4 three times that of control TTR. Exons 2, 3, and 4 (representing greater than 97% of the coding sequence) of the TTR 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 TTR and restriction digestion with Fnu 4H I confirmed that five affected family members with increased binding of 125I-T4 to TTR are heterozygous for the threonine 109 substitution that increases the affinity of this abnormal TTR for T4.

Amino Acid Sequence↗
PubMed1984

Effect of chloride on serum thyroxine binding in familial dysalbuminemic hyperthyroxinemia.

Chloride ion is known to inhibit the T4-albumin interaction in normal serum. To determine the extent of this effect on T4 binding to albumin in patients with familial dysalbuminemic hyperthyroxinemia (FDH), the serum percent free T4 (FT4) was measured by equilibrium dialysis in 0.1 M phosphate buffer, pH 7.4, and in phosphate buffer with 0.14 M NaCl (phosphate-saline buffer) in patients with FDH, normal subjects, and women in the third trimester of pregnancy, who served as a population with high serum T4-binding globulin concentrations. The FT4 was calculated as the product of the percent FT4 and total T4 concentration. The mean values of serum FT4 were similar among the three groups when equilibrium dialysis was performed in phosphate buffer. When the assay was carried out in phosphate-saline buffer, the mean percent FT4 in each group was higher than that obtained in phosphate buffer, resulting in higher mean serum FT4 concentrations. However, the mean serum FT4 in normal subjects and pregnant women remained similar. The increase in percent FT4 in phosphate-saline buffer was proportionally greater in the patients with FDH, and therefore the mean serum FT4 in these patients was significantly higher than that of normal subjects when phosphate-saline buffer was used (2.67 +/- 0.07 (SE) vs. 1.80 +/- 0.09 ng/dl, P less than 0.001), and all FT4 values were above the normal range. It is concluded that chloride ion inhibits serum T4 binding in patients with FDH more than it does in normal subjects, perhaps due to the fact that albumin plays a much greater role in overall T4 binding in these patients.

Chlorides↗
PubMed1984

Thyroxine distribution and metabolism in familial dysalbuminemic hyperthyroxinemia.

We studied two families with familial dysalbuminemic hyperthyroxinemia (FDH), a recently described entity characterized by marked elevation of serum T4 due to increased binding of T4 to albumin. The seven affected subjects had elevated serum total T4 levels (range, 15.3-25.2 micrograms/dl; normal, 4.5-11.0 micrograms/dl), but normal serum free T4 levels, as measured by equilibrium dialysis. Their serum T3 levels ranged from 1.40-2.46 ng/ml (normal, 0.9-2.0 ng/ml). The proportion of T4 associated with serum albumin was increased approximately 4-fold in the affected subjects, as shown both by reverse flow paper electrophoresis and immunoprecipitation of albumin-bound T4 with antihuman serum albumin. In vivo T4 kinetic studies were performed in the two index subjects to assess the effects of the increased binding of T4 to albumin on the in vivo transport, distribution, and disposal of T4. Compared to values in normal subjects, the MCR of T4 was decreased by about 50%, and its total body (extrathyroidal) pool size was increased by approximately 50%; the T4 production rate was normal. The extracellular T4 pool size was increased by about 100% in the FDH subjects, but the rapidly exchangeable intracellular T4 pool size was normal. The unidirectional T4 clearance rate from plasma into the rapidly exchangeable cellular compartment was reduced by approximately 50%, but the absolute rate of T4 flux from plasma into the cellular compartment was normal. Thus, the in vivo kinetic data indicate that the increased plasma binding of T4 in FDH alters the distribution of T4 in favor of the extracellular compartment, retards the fractional rate of transfer of T4 into cells, and slows the metabolic clearance of T4. However, the absolute rate of T4 flux into the rapidly exchangeable cellular compartment, the intracellular T4 pool size, and the T4 disposal rate are all normal in FDH, consistent with the normal serum concentrations of free T4 and the eumetabolic state of these individuals.

Adult↗
PubMed1985

Heterogeneity of thyroxine binding by serum albumins in normal subjects and patients with familial dysalbuminemic hyperthyroxinemia.

The nature and properties of the T4-binding albumins in the sera of normal subjects and patients with the syndrome of familial dysalbuminemic hyperthyroxinemia (FDH) were investigated by means of isoelectric focusing in polyacrylamide gels. Albumins isolated from normal sera and sera of patients with FDH displayed multiple protein bands, with isoelectric points between 4.65 and 5.75, and protein patterns were the same in the two groups. In normal albumin, [125I]T4 was consistently localized in two bands, termed B1 and B2, whose isoelectric points (pIs) were 5.44 +/- 0.03 and 5.31 +/- 0.02 (mean +/- SE), respectively. Occasionally, binding of far smaller proportions of [125I]T4 was seen in two additional bands of lower pI (5.22 +/- 0.03 and 4.97 +/- 0.07), termed B3 and B4, respectively. In FDH albumin, [125I]T4 was also localized in four bands whose PIs were almost identical to those of B1-B4 in normal albumin. In FDH albumin, however, bands corresponding to B1 and B2 bound only a minor fraction of [125I]T4, the great majority being bound by bands corresponding to B3 and B4, especially the latter. Identity of the four T4-binding albumins in normal and FDH albumin was suggested by their virtually identical pIs in both types of albumin, by the emergence or intensification of the B3 band in both after extraction of endogenous T4, and by the finding that an 125I-labeled derivative of T4 used in a commercial one-step assay for serum free T4 was bound by the B4 band in both normal and FDH albumin, though more intensely in the latter. Treatment of FDH albumin with increasing concentrations of dithiothreitol (DTT; 0.1-5.0 mM) caused a progressive loss of [125I]T4 binding by B3 and B4, leaving [125I]T4 bound by B1 or B2, and had little effect on the binding of [125I]T4 by B1 and B2 in normal albumin. These effects of DTT appeared to correlate well with earlier dialysis studies at physiological pH which revealed that the same concentrations of DTT decreased or abolished the high affinity binding of T4 in FDH albumin but had little effect on the residual lower affinity binding of T4 in FDH albumin or that characteristic of normal albumin. These findings suggest that T4 binding patterns evident during isoelectric focusing of albumin at low pH have relevance to binding of T4 by albumins at physiological pH.(ABSTRACT TRUNCATED AT 400 WORDS)

Alkylation↗
PubMed1985

Hepatic bioavailability of thyroxine and testosterone in familial dysalbuminemic hyperthyroxinemia.

The bioavailability of [125I]T4 or [3H]testosterone in serum obtained from normal subjects and from subjects with familial dysalbuminemic hyperthyroxinemia (FDH) was studied with a portal vein injection technique in ketamine-anesthetized rats. In the present studies this technique was modified by performing uptake measurements in the presence of serum loaded with either 25 microM T4 or 1 microM testosterone. Loading of serum with these high concentrations displaced the labeled hormone from the lower capacity globulin or prealbumin-binding sites to the high capacity albumin or dysalbumin-binding sites, and allowed for the analysis of hormone availability in liver when the labeled hormone was delivered to the tissue bound either to albumin or to dysalbumin binding sites. In the presence of normal serum, 33 +/- 3% (SE) of T4 was available to rat liver, as opposed to 20 +/- 2% for FDH serum. When normal serum was loaded with 25 microM T4, the bioavailable T4 increased to 97 +/- 2%, consistent with the availability of T4 bound to albumin. However, the hepatic bioavailability of T4 in the presence of 25 microM T4 in FDH serum was only 33 +/- 4%. Testosterone bioavailability was similar in normal and in FDH sera, and was 49 +/- 7% in the absence and 99 +/- 4% in the presence of 1 microM testosterone. These studies suggest that T4 bound to the FDH albumin binding site is not readily available for entry into liver, whereas T4 bound to the normal albumin binding site is freely available for uptake in vivo. The differential bioavailability of T4 is compatible with the model that the normal and FDH binding sites are situated on different parts of the albumin molecule, and that only T4 bound to the normal binding site is freely available for delivery to the liver.

Animals↗
PubMed1986

Sex hormone-binding protein in hyperthyroxinemic patients: a discriminator for thyroid status in thyroid hormone resistance and familial dysalbuminemic hyperthyroxinemia.

Sex hormone-binding globulin (SHBG) levels in serum are affected by thyroid status; hyperthyroidism is associated with high SHBG levels, whereas hypothyroid patients have low or normal SHBG levels. This study was undertaken to test the usefulness of SHBG determinations to define the thyroid status in two hyperthyroxinemic states: thyroid hormone resistance (THR) and familial dysalbuminemic hyperthyroxinemia (FDH). Serum SHBG levels were determined in 193 patients and 26 normal subjects using an IRMA-type RIA. In the control group, the mean values in women (58.9 nmol/liter) and men (32.7 nmol/liter) were significantly different (P less than 0.001). In adult subjects with THR, SHBG levels were within the normal range, with mean values of 54.8 nmol/liter (range, 28.7-82.5 nmol/liter) in women and 18 and 20 nmol/liter in two men. In FDH subjects, the mean SHBG levels did not differ from the normal values; they averaged 60.7 nmol/liter in women and 42.3 nmol/liter in men. From these data we conclude that in THR and FDH, free T4 levels elicit an appropriate hepatic response corresponding to the euthyroid status of these subjects. SHBG determination may, therefore, serve as an in vitro test for end-organ sensitivity to thyroid hormones.

Drug Resistance↗
PubMed1988

Euthyroid hyperthyroxinemia due to a generalized 5'-deiodinase defect.

We studied an 11-yr-old girl with asymptomatic hyperthyroxinemia, who remained euthyroid and healthy for 5 yr of follow-up. Besides having elevated serum T4 concentrations, her serum free T4 concentrations were consistently elevated, as measured by three different methods, including equilibrium dialysis and ultrafiltration. Serum total and free T3 concentrations were in the low normal range, and serum 3,5-diiodothyronine (3,5-T2) levels were low, suggesting reduced 5'-deiodination of both T4 and T3. Serum total and free rT3 and total and free 3', 5'-T2 concentrations were all markedly elevated, whereas serum total and free 3,3'-T2 were low, suggesting unaltered 5-deiodination of T4 to rT3 and of rT3 to 3',5'-T2 in combination with reduced 5'-deiodination of rT3 and 3',5'-T2. The girl had a small diffuse goiter, her serum TSH response to TRH was exaggerated, and thyroid radioiodine uptake was elevated, suggesting slightly increased TSH secretion and, consequently, increased thyroid secretion. Both T3 and T4 administration resulted in suppressed basal as well as TRH-stimulated serum TSH concentrations, and radioiodine uptake was suppressed during T3 administration. Our data suggest reduced activity of several (all?) peripheral 5'-deiodination pathways, including possibly also thyrotroph T4 5'-deiodination. Thus, this girl seems to have a previously unrecognized syndrome of generalized 5'-deiodinase deficiency.

Child↗
PubMed1980

Amphetamine-induced hyperthyroxinemia.

Four patients had high serum thyroxine (T4) concentrations during periods of heavy amphetamine abuse. After amphetamine was withdrawn, serum T4 returned to normal. Administration of amphetamine to monkeys induced a rise in serum T4; in this model the high T4 level appeared to be caused by increased serum thyrotropin. The mechanism of this effect is unclear but is presumably mediated via the hypothalamus. Awareness of transient hyperthyroxinemia due to amphetamine may allow the physician to avoid confusion with true thyrotoxicosis.

Adult↗
PubMed1982

Familial hyperthyroxinemia due to abnormal thyroid hormone binding.

A patient had an elevated serum total thyroxine (T4) free thyroxine (free T4), free T4 index, and T4/thyroxine-binding globulin ratio. The serum triiodothyronine (T3), as well as the thyrotrophin response to thyrotrophin-releasing hormone was normal and consistent with the clinical euthyroid status. The basis for the elevated serum total T4, free T4 index, and T4/thyroxine binding globulin is the abnormally enhanced binding of thyroid hormone by albumin, or by an anomalous protein migrating with a mobility similar to albumin as determined in paper electrophoretic systems. The abnormal T4 protein binding was also seen in several members of the patient's family indicating that the condition was familial. A new type of serum T4 protein binding abnormality that results in hyperthyroxinemia may falsely indicate thyrotoxicosis in clinically euthyroid subjects.

Adult↗
PubMed1983

Euthyroid hyperthyroxinemia.

An increasing number of disorders that may cause hyperthyroxinemia without thyrotoxicosis have been recognized in recent years. These include acquired and inherited abnormalities of serum thyroid-hormone-binding proteins, peripheral resistance to thyroid hormones, acute nonthyroidal illness, acute psychiatric illness, and some drug-induced conditions associated with nonthyrotoxic elevations of serum thyroxine. In addition to the laboratory finding of elevated serum thyroxine levels, many of these syndromes are also accompanied by abnormalities in triiodothyronine and free thyroid hormone levels, as well as unresponsiveness of thyroid-stimulating hormone to thyrotropin-releasing hormone, all of which further erroneously indicate a diagnosis of thyrotoxicosis. An awareness of these syndromes and alterations in the results of thyroid function tests that accompany them is important to prevent a misdiagnosis of hyperthyroidism and inappropriate therapy.

Amiodarone↗
PubMed1986

Concentration of free thyroxin in serum of a patient with euthyroid hyperthyroxinemia secondary to increased thyroxin-binding prealbumin: results by various methods compared.

We used various kits to measure free thyroxin (T4) in serum from a patient with the very rare syndrome of euthyroid hyperthyroxinemia secondary to increased thyroxin-binding prealbumin in serum. This patient's free T4 by equilibrium dialysis was 13 ng/L (normal 9-21), whereas the free-T4 index was 18.6 (normal 5.5-11.5). Using six different commercial methods, the last three listed being T4-analog methods, we measured the serum free T4 in this patient. The mean +/- SD (and normal range) free-T4 concentrations (ng/L) measured were: GammaCoat, Two-Step, 19.2 +/- 4.5 (6.9-26.9); Liquisol, 17.8 +/- 3.0 (12.4-20.8); Immo Phase, Two-Step 26.8 +/- 0.3 (12.4-21.2); GammaCoat, Single-Step, 19.7 +/- 5.7 (10.3-21.0); Immo Phase, Single-Step, 27.7 +/- 0.9 (8.6-25.0); and Amerlex, 14.1 +/- 0.6 (5.3-14.1). In four patients with familial dysalbuminemic hyperthyroidism, in whom the serum T4 by equilibrium dialysis was normal, all three T4-analog methods gave results far exceeding normal (greater than 50 ng/L).

Humans↗
PubMed1986

Transient hyperthyroxinemia in symptomatic hyponatremic patients.

Twenty-two patients with severe hyponatremia were divided into 12 patients with and ten without associated neurologic manifestations (groups 1 and 2, respectively). Marked hyperthyroxinemia was demonstrated in seven patients in group 1 but in none in group 2. The triiodothyronine concentration was also higher than normal in two patients in group 1. All serum iodothyronine concentrations in group 1 were significantly higher than in group 2. Thyrotropin and thyroxine-binding globulin levels were normal in both groups. The differences between groups were apparent only in the acute phase, and there were no clinical manifestations of hyperthyroidism. All iodothyronine concentrations returned to normal within two weeks after the correction of the hypo-osmolar disorder. Our results indicate that a transient asymptomatic increase in serum iodothyronine levels occurs during hyponatremia. Thus, thyroid test results should be interpreted cautiously in patients with acute, severe, symptomatic hyponatremia.

Aged↗
PubMed1984

Familial dysalbuminemic hyperthyroxinemia: a study of four probands and the kindred of three.

We investigated four probands, and the kindred of three, with familial dysalbuminemic hyperthyroxinemia, using the one- and two-step tests for free thyroxin and other thyroid-function tests. The results indicate that this is an autosomal dominant trait. The discovery of eight cases in our patient population, which represents about 4% of our hyperthyroxinemic patients (8/320), during eight months indicates that this aberration is more common than suspected. Its importance lies in the misinterpretation of test results and the consequent inappropriate treatment for thyrotoxicosis.

False Positive Reactions↗
PubMed1993

Factitious hyperthyroxinemia due to a monoclonal IgA in a case of multiple myeloma.

A clinically euthyroid 53-year-old woman with an IgA-lambda-secreting multiple myeloma presented with increased serum concentrations of thyroid hormones. Laboratory studies revealed increased total thyroxine (T4) and triiodothyronine (T3) concentrations, a high-normal free T4 concentration, and a normal basal thyrotropin (TSH) concentration with a normal response to thyroliberin (TRH). Her serum concentration of IgA was 11,040 mg/L (normal range 900-4500 mg/L) and immunoelectrophoresis revealed it to be monoclonal. This monoclonal IgA bound both T4 and T3, as determined by serum immunoelectrophoresis and direct binding studies. Immunoelectrophoresis in the presence of [125I]T4 or [125I]T3 localized the radiolabeled iodothyronines to a band corresponding exactly to the precipitin arc of the monoclonal IgA. We performed direct binding studies with IgA purified by affinity chromatography with the lectin jacalin. Purified IgA (50 micrograms) bound both [125I]T4 (12.3%) and [125I]T3 (2.7%) specifically and in a dose-dependent manner. Scatchard analysis of competitive-binding data utilizing [125I]T4 and unlabeled T4 revealed a Kd of 2.2 x 10(-7) mol/L. The binding capacity for T4 was approximately 7 mumol/L. Thus, in this case of IgA-secreting myeloma, the monoclonal IgA acts as an additional thyroid hormone-binding protein in serum that interferes in the T4 and T3 RIAs. This is the first report of a monoclonal IgA producing an apparent euthyroid hyperthyroxinemia.

Antibodies, Monoclonal↗
PubMed1994

Hyperthyroxinemia after surgery for primary hyperparathyroidism.

Episodes of transient thyrotoxicosis after surgery for primary hyperparathyroidism have previously been described, and surgical trauma to the thyroid gland has been suggested as an etiologic factor. However, there are several links between the thyroid and parathyroid hormonal systems, and therefore other explanations are possible as well. In this study we investigate pre- and postoperative serum levels of thyroid hormones in 20 patients operated upon because of primary hyperparathyroidism. The mean (SD) serum levels of T4 increased from 16(2) pmol/l preoperatively to 21(6) pmol/l on the fourth postoperative day (P < 0.01), and four (20%) of the patients developed biochemical thyrotoxicosis in the immediate postoperative period. The serum levels of T4 on the fourth postoperative day correlated highly with preoperative serum levels of PTH (r = 0.75; P < 0.001). This suggests that biochemical thyrotoxicosis in the immediate postoperative period after operation for primary hyperparathyroidism is not uncommon and could be related to the disease rather than to surgical trauma.

Adult↗