Defects of Thyroid Hormone Transport in Serum

Inherited abnormalities of thyroid hormone-binding proteins are not uncommon and can predominate in some ethnic groups. They alter the amount of iodothyronines present in serum and, although the concentration of free hormones remains unaltered, routine measurement can give erroneous results. With a single exception, inherited defects in thyroxine-binding globulin (TBG), are X-chromosome linked and thus, the full phenotype is expressed mostly in males. Partial TBG deficiency is more common than complete efficiency. High frequency of variants TBGs have been identified in African Blacks, Australian Aborigine and Eskimos. Most defects producing TBG deficiency are caused by mutations in the structural gene. However, inherited X-linked partial deficiency can occur as the consequence of mutations of a gene enhancer. Inherited forms of TBG excess are all cases by gene duplication or triplication. Mutations in the transthyretin (TTR) gene producing a molecule with increased affinity for T4 are relatively rare. A variant TTR produces transient hyperthyroxinemia during non-thyroidal illness. Mutations of the human serum albumin (HSA) gene produce increased concentration of serum T4, a condition known as familial dysalbuminemic hyperthyroxinemia (FDH). They are relatively more common in individuals of Hispanic origin. They cause an increase in serum T4 owing to increased affinity for this iodothyronine but high concentrations in free T4 observed in direct measurement by some commercial methods are erroneous. A variant with increased affinity for T3 has been also identified. INTRODUCTION Abnormalities in the serum proteins that transport thyroid hormone do not alter the metabolic state and do not cause thyroid disease. However, they do produce alterations in thyroid hormone concentration in serum and when unrecognized have lead to inappropriate treatment. When the abnormality is the consequence of altered synthesis, secretion or stability of the variant serum protein, the free thyroid hormone level estimated by most of the clinically available techniques remains within the range of normal. In contrast, when the defect results in a significant alteration of the affinity of the variant protein for the hormone, estimates of the free thyroid hormone level give often erroneous results and thus, it is prudent to measure the free hormone concentration by more direct methods such as equilibrium dialysis or ultrafiltration. This is also true in cases of complete TBG deficiency, in whom the estimation of free thyroid hormone level in serum by indirect methods, or using iodothyronine analogs as tracers, can also give erroneous results. The existence of inherited defects of serum transport of thyroid hormone was first recognized in 1959 with the report of TBG-excess by Beierwaltes and Robbins (1). Genetic variants for each of the three major thyroid hormone transport proteins have been since described and in recent years, the molecular basis of a number of these defects has been identified (2). Clinically, these defects usually manifest as either euthyroid hyperthyroxinemia or hypothyroxinemia and more rarely, isolated hypertriiodothyroninemia (3). Associated abnormalities such as thyrotoxicosis, hypothyroidism, goiter and familial hyperlipidemia are usually coincidental (4). However, individuals with thyroid disorders are more likely to undergo thyroid testing leading to the fortuitous detection of a thyroid hormone transport defect. THYROXINE-BINDING GLOBULIN (TBG) DEFECTS Familial TBG abnormalities are inherited as X-chromosome linked traits (5,6), compatible with the location of the TBG gene on the long arm of the X-chromosome (Xq22.2) (7,8). This mode of inheritance also suggests that the defects involve the TBG gene proper, rather than the rate of TBG disposal, as long ago postulated (5). The normal, common type TBG (TBG-N or TBG-C), has a high affinity for iodothyronines [affinity constants (Ka): 10-10 M-1 for T4 and 10-9 M-1 for T3] and binds 75% of the total T4 and T3 circulating in blood. Thus, with a single exception [HSA R218P (9,10), see below], among the inherited abnormalities of thyroid hormone transport proteins, those involving the TBG molecule produce usually more profound alterations of thyroid hormone concentration in serum. Clinically TBG defects are classified according to the level of TBG in serum of affected hemizygotes (XY males or XO females, that express only the mutant allele): complete TBG deficiency (TBG-CD), partial TBG deficiency (TBG-PD) and TBG excess (TBG-E). In families with TBG-CD, affected males have no detectable TBG and carrier females (mothers or daughters) have on the average half the normal TBG concentration (4). In families with partially TBG deficient males, the mean TBG concentration in heterozygous females is usually above half the normal. Serum TBG concentration in males with TBG-E is 2 to 4-fold the normal mean and that in the corresponding carrier females, is slightly higher than half that of the affected males. These observations indicate an equal contribution of cells expressing the normal and mutant TBG genes. On rare occasions, selective inactivation of the X-chromosome has been the cause the manifestation of the complete defect (hemizygous phenotype) in heterozygous females (11). Inherited TBG defects can be further characterized by the level of denatured TBG (dnTBG) in serum and the physicochemical properties of the molecule. The latter can be easily determined without the need of purification. These properties are: (a) immunologic identity; (b) isoelectric focusing (IEF) pattern; (c) rate of inactivation when exposed to various temperatures and pH; and (d) affinity for the ligands, T4 and T3. More precise identification of TBG defects requires sequencing of the TBG gene. MiP a subject with TBG-CD The proposita, a phenotypic female, was 13 years old when first seen because of retarded growth, amenorrhea and absence of secondary sexual traits. She was the first sibling of a second marriage for both parents. The family included a younger brother and four older half-siblings, two maternal and two paternal. The proposita was born to her 30-year-old mother after full-term, uncomplicated pregnancy. Infancy and early childhood development were normal until 4 years of age when it became apparent that she was shorter than her peers. She was 12 years of age when a low protein bound iodine (PBI, then a measure of T4) of 2.2 μg/dl (normal range 4.0-8.0) was noted and treatment with 120 mg of desiccated thyroid (equivalent to 200μg L-T4) daily was initiated. Since, during the ensuing 6 months, no change in her growth rate occurred and because PBI remained unchanged (2.0 μg/dl), the dose of desiccated thyroid was increased to 180 mg/day. This produced restlessness, perturbed sleep and deterioration of school performance necessitating discontinuation of thyroid hormone treatment. No family history of thyroid disease or short stature was elicited and the parents denied consanguinity. On physical examination, the patient appeared younger than her chronological age, was short (137 cm) and showed no signs of sexual development. She had a webbed neck, low nuchal hairline, bilateral eyelid ptosis, shield-shaped chest, increased carrying angle and short 4th metacarpals and metatarsals. The thyroid gland was normal in size and consistency. Buccal smear was negative for Barr bodies and karyotyping revealed 45 chromosomes consistent with XO Turner's syndrome. No chromosomal abnormalities were found in lymphocytes from the mother and father. Bone age was 12 years and X-ray of the scull showed a mild degree of hyperteliorism. PBI and butanol extractable iodine were low at 2.0 and 1.8 μg/dl, respectively. Resin-T3 uptake was high at 59.9% (normal range 25-35%) indicating reduced TBG-binding capacity. A 24-hour thyroidal radioiodide uptake was normal at 29%, basal metabolic rate was +20% (normal range -10 to +20) and TG autoantibodies were not present. Serum cortisol was normal as were the responses to ACTH and metyrapone. Basal growth hormone concentration was normal at 8.0 ng/ml which rose to 32 ng/ml following insulin hypoglycemia. Studies were carried out in all first degree relatives and the propositus was treated cyclically with diethylstilbestrol which produced withdrawal uterine bleeding and gradual breast development. Five family members, in addition to the proposita had thyroid function tests abnormalities. Two were males and three females. The two males (maternal grand father and maternal half-brother) and the proposita had the lowest PBI levels and undetectable T4-binding to serum TBG. In contrast, the three females (mother, maternal aunt and maternal half-sister) had a lesser reduction of their PBI and T4binding capacity to TBG approximately one-half the normal mean value. The two sons of the affected grandfather (maternal uncles to the proposita) had normal PBI and T4-binding to TBG. No interference with T4-binding to TBG or other serum protein abnormalities were found in affected members of the family. In vivo T4 kinetic studies revealed a rapid extrathyroidal turnover rate but normal daily secretion and degradation, compatible with their eumetabolic state.