Abnormal Thyroid Hormone Transport

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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 any 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 T4-binding 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.


The incidental identification of thyroid tests abnormalities in the propositus is typical for most subjects with TBG deficiency as well as TBG excess. So is the initial unnecessary treatment; though less frequent with the routine measurement or estimation of free T4. The inherited nature of the defect is suspected by exclusion of factors known to cause acquired TBG abnormalities and should be confirmed by the presence of similar abnormalities in members of the family. The absence of male to male transmission and the carrier state of all female offspring of the affected males is a typical pattern of X-chromosome linked inheritance. This is further supported by the complete TBG deficiency in individuals having a single X chromosome (males and the XO female) and only partial TBG deficiency in carrier XX females.

Since the publication of this family in 1968 (12), the cause of the TBG defect was identified. From the mutation identified in the TBG gene of this family [TBG Harwichport (TBG-CD H)], it can be deduced that the molecule is truncated, missing 12 amino acids at the carboxyl terminus (13).

Forty two TBG variants have been so far identified and in 34 the precise defect has been determined by gene analysis. Their primary structure defect, some of their physical and chemical properties and the resulting serum T4 concentrations are summarized in table 1 and figure 1 .

Complete Deficiency of TBG (TBG-CD): TBG-CD is defined as undetectable TBG in serum of affected hemizygous subjects or a value lesser than 0.03% the normal mean; the current limits of detection using the most sensitive radioimmunoassay (RIA) being 5ng/dl (23). The prevalence is approximately 1:15,000 newborn males. Twenty two TBG variants having this phenotype have been characterized at the gene level. These are shown in table 1 that also contains references to the original publications. Sixteen of the 22 TBG-CDs have truncated molecules. In thirteen variants, early termination of translation caused by a single nucleotide substitution (TBG-CDP1, TBG-CDP2, TBG-CDB and TBG-CDT2) or by a frame shift due to a nucleotide deletion (TBG-CDY, TBG-CDN, TBG-CDNi, TBG-CD6, CD-PL, TBG-CD7, TBG-CD8, and TBG-CDJ) or deletion of 19 nucleotides (TBG-CDH). In four variants mutations occurred in introns close to splice sites (TBG-CDMi, TBG-CDK, TBG-CDL and TBG-CDJa). A mutation at the acceptor splice junction caused also a frame shift producing early termination of translation in TBG-CDK (21). In contrast a nucleotide substitutions in the 5′ donor splice site of intron IV (TBG-CDL and TBG-CDJa), resulted in a complete splicing of exon 3, also producing a truncated molecule (26) and personal observation. A similar mechanism is likely responsible for CD in TBG-CDMi, though direct experimental prove was not provided (14). Single amino acid substitution was the cause of CD in four families (TBG-CDT1, TBG-CD5, TBG-CDP3 and TBG-CDKo). In TBG-CD5 Leucine-227 with a proline was shown to cause aberrant post-translational processing (38). One TBG variant (TBG-CDNI), with two nucleotides deleted close to the carboxyl terminus, the resulting frame shift predicts an extension of the molecule by the addition of 7 nonsense residues (31). TBG-CDJ has been so far identified only in Japanese but its allele frequency in the population remains unknown (29, 45) ( Table. 1 ).

Table 1. TBG Variants and Gene Mutations
TBG NAME Abbreviated name Intronexon CODON* WT Variant WT Variant References
Complete Deficiency (CD)
Milano (fam A) CDMi† IVS 1 fs 5′ DSS gtaagt gt t aagt (14)
Portuguese 1 (pt A) CDP1 1 23 S (Ser) X (OCH) TCA T A A (15)
Yonago CDY 1 28-29 fs -51 D F X (OPA) GA(CT)TT GA A TT (16)
Negev (Bedouin) CDN 1 38 fs -51 T (Thr) X (OPA) ACT T del (17, 18)
Nikita (fam B) CDNi 1 50 fs -51 P (Pro) X (OPA) CCT T del (14)
Taiwanese 1 CDT1† 1 52 S (Ser) N (Asn) AGC A A C (19)
no name CD6 1 165 fs 168 V (Val) X (OCH) GTT T del (20)
Kankakee CDK IVS 2 188 fs 195 3′ ASS X (OPA) agCC g gCC (21)
Poland CDPL 2 201 fs 206 GAC X (OCH) GAC G del (22)
Portuguese 2 (pt B) CDP2 2 223 Q (Gln) X (OCH) CAA T AA (15)
No name CD5† 2 227 L (Leu) P (Pro) CTA C C A (23)
Portuguese 3§ CDP3 2 233 N (Asn) I (Ile) ACC A T C (24)
Buffalo CDB 3 280 W (Trp) X.(AMB) TGG T A G (25)
Taiwanese 2 CDT2 3 280 W (Trp) X.(OPA) TGG TG A (19)
Lisle CDL IVS 4 280 fs -325 5′ DSS X (OPA) gtaaa g g aaa personal observation
Jackson (fam K) CDJa IVS 4 280 fs -325 5′ DSS X (OPA) gtaaa gtaa g (26)
Harwichport CDH 4 282 fs -384 Y (Tyr) X (OPA) TAT 19nt del (12, 13, 27)
No name CD7 3 283 fs -301 L (Leu) X (OPA) TGT G del (13)
No name CD8† 4 329 fs -374 A (Ala) X (OPA) GCT G del (13)
Japan CDJ 4 352 fs -374 L (Leu) X (OPA) CTT C del (28, 29)
Kyoto§ CDKo 4 370 S (Ser) F (Phe) TCT T T T (30)
NeuIsenburg CDNl 4 384 fs -402 L (Leu) 7 aa add CTC TC del (31)
Partial Deficiency (PD)
Allentown PDAT 1 -2 H (His) Y (Tyr) CAC T AC (32)
San Diego PDSD† 1 23 S (Ser) T (Thr) TCA A CA (33-35)
Gary PDG 1 96 I (Ile) N (Asn) ATC A A C (36)
Montréal PDM 1 113 A (Ala) P (Pro) GCC C CG (37, 38)
Aborigine PDA† 2 191 A (Ala) T (Thr) GCA A CA (39, 40)
Glencoe PDGe 2 215 V (Val) G (Gly) GTG G G G (41)
Quebec PDQ† 4 331 H (His) Y (Tyr) CAT T AT (37, 42)
Japan-Kumamoto PDJ/K 4 363 P (Pro) L (Leu) CCT C T T (43, 44)
Other variants
Polymorphic Poly 3 283 L (Leu) F (Phe) TTG T T T (23, 45)
Slow S 1 171 D (Asp) N (Asn) GAC A AC (46-48)
Chicago Cgo 3 309 Y (Tyr) F (Phe) TAT T T T (49, 50)
* Codon numbering from fist amino acid of the mature protein. The 20 amino acids of the signal peptide are numbered -1 to -20, from N- to C-terminus. The codon at the site of mutation is followed by the codon at the site of termination of translation.† coexistence of TBG Poly§ complete deficiency is uncertain as the TBG assay used was unable to detect values <10% the mean normal.¶ Also a silent mutation at codon 55: GCA -> GCG.del, delete; add, addition

aa, amino acid

fs, frame shift

Pt, patent; fam, family

IVS, intervening sequence or intron

ASS, acceptor splice site

DSS, donor splice site


Partial Deficiency of TBG (TBG-PD): This is the most common form of inherited TBG deficiency having a prevalence of 1:4,000 newborn. Identification of heterozygous females by serum TBG measurement may be difficult because levels often overlap the normal range. In contrast to variants with complete TBG deficiency all TBG-PDs have missense mutations. it is possible that three of the four variants with single amino acid substitutions have also partial deficiency which was not identified owing to the low sensitivity of routine assays for the measurement of TBG. Eight different mutations, producing a variable degree of reduction of TBG concentration in serum, have been identified. They are listed in table 1 . In addition, some of these variants are unstable (TBG-PDG, TBG-PDA, TBG-PDSD, TBG-PDM and TBG-PDQ) or have lower binding affinity for T4 and T3 (TBG-PDG, TBG-PDA, TBG-PDSD, TBG-PDM and TBG-PDQ) and some exhibit an abnormal migration pattern on IEF electrophoresis (TBG-PDG, TBG-PDM, and TBG-PDQ) ( Fig. 1 ). Variants with decreased affinity for T4 and T3 have a disproportionate reduction in hormone concentration relative to the corresponding serum TBG level ( Fig. 2 ) and estimations of the free hormone levels by any of the index methods gives erroneous results (35, 54). One of these variants, TBG-PDA, is found with high frequency in Australian Aborigines (allele frequency of 51%) (40).

”]A unique family with TBG-PD has been described in which inheritance of the partial deficiency was autosomal dominant with transmission of the phenotype from father to son (56). The concentration of TBG in affected males and females was about one half the normal mean value. The TBG had normal affinity for T4. normal IEF and heat lability. No sequence changes were found in the entire coding arias of the gene or in the promoter region. Although the mechanism of TBG-CD in this family is unknown an abnormality in one of the factors regulating TBG gene transcription is a distinct possibility.

Finally, in four families, two with TBG-CD (fam H, and, fam Ns) and two TBG-PD (fam W and fam Aw) no mutations were identified in the TBG gene. All four families the defects were X-chromosome-linked and sequencing covered the coding and intervening regions as well as the promoter, up to 5,000 base pairs upstream of the transcription start site (26,Narendran, 2003 #5727) and personal observations.

TBG Excess (TBG-E): TBG-E has a lower prevalence than TBG deficiency, with values obtained from neonatal screening programs from 1:6,000 to 1:40,000 (57, 58). Considering that some newborn may have non-inherited, transient TBG excess, a conservative overall estimate of inherited TBG-E would be 1:25,000 (59). Early sequencing of the coding and promoter regions of subjects with TBG-E failed to show any defects (60). However, in 1995, Mori et al (61) found that gene amplification was the cause of TBG-E in two families. Gene triplication and duplication were demonstrated by gene dosage studies using HPLC measurements of the PCR -amplified product. As expected, hemizygous affected males had approximately 3- and 2-fold the average normal serum TBG concentration, respectively. The presence of multiple TBG gene copies in tandem was confirmed by in situ hybridization of prometaphase and interphase chromosomes from an affected male.

TBG Variants with Unaltered TBG Concentrations in Serum: Five TBG variants have been identified that present with normal or clinically insignificant alterations in their concentration in serum. Four occur with high frequency in some population groups and thus, can be considered as polymorphic. TBG-Poly ( Fig. 1 ), with no alterations of its physical or biological properties, has been detected in 16% and 20% of the French Canadian and Japanese populations, respectively (23, 45). TBG-S exhibits a slower mobility on polyacrylamide gel electrophoresis and cathodal shift on IEF (46, 47), owing to the loss of a negative change due to the replacement of the normal Asp171 by Asn (48) ( Figs. 1 and 3 ). It has an allele frequency of 5 to 16% in Black populations of African origin and 2 to 10% in Pacific Islanders. The molecular structure of two other polymorphic TBG variants has not been identified. TBG-F has an allele frequency of 3.2% in Eskimos residing on the Kodiac and St. Lawrence islands. It has a slight anodal (fast) mobility on IEF (62). TBG-C1 has been recently identified in subjects inhabiting two Mali village (63). It has a small cathodal shift on IEF and an allele frequency of 5.1%. TBG-Cgo, resistant to high temperatures (50), has normal affinity for T4 and T3. All SERPINs except human TBG have a Phe at a position corresponding to Tyr309. Structure modeling suggests that the replacement of the normal Tyr309 by Phe in TBG-Cgo, ties the internal -helix hI1 to the molecule, thus stabilizing its tertiary structure (49). However, more recent studies using recombinant TBG–Cgo showed that the molecule exists in loop expelled conformation. However, when exposed at 37°C, the protein readily converts to a more stable loop inserted conformation explaining its subsequent enhanced heat stability, as observed in vivo (64).

”]Biological Consequences of Structural Changes Caused by Mutations in the TBG Gene: The mechanisms whereby structural abnormalities of the TBG molecule produce the variant phenotypes have been investigated by expression of some of these molecules in living cells. Contrary to previous speculation, increased extracellular degradation due to instability is a rare cause reduced concentration of the variant TBG in serum (34). More commonly, intracellular retention and degradation of the defective TBG molecules is responsible for their presence in low concentrations in serum (38, 44, 51, 65). Of note is the full intracellular retention of TBG-CD5 despite synthesis in normal quantities. A single amino acid substitution in TBG-CD5 is sufficient to alter its tertiary structure and thus prevent export. The same finding in the case of TBG-CDJ has been traced to its retention within the endoplasmic reticulum. Furthermore, the increased amount of GRP78 mRNA in cells transfected with TBG-PDJ suggests that association of this TBG variant with the GRP78 molecular chaperon is responsible for its impaired secretion (44). The variant TBG-AL is unique and important as it provides information about the function of the signal peptide. The resulting variable decrease in the serum TBG concentration associated with diminished in vitro secretion is compatible with impaired cotranslational processing (32).

Several speculations regarding the properties of variant TBGs have been confirmed based on the recent elucidation of the TBG structure by X-ray crystallography (66). The reduced ligand-binding of TBG-SD (34, 35) can be explained by the direct proximity of the amino acid substitution to the binding pocket. Indeed, the metyl group of the side chain of Thr23, replacing the normal Ser, will sterically hinder the binding of T4. Similarly, in TBG-A, the replacement of Ala191 by Thr (40) perturbs the H-bounds that stabilizes the binding pocket, leading to the reduced T4 binding. In contrast, the loss of His331 in TBG-Q (H331Y) (37, 42) allows unrestricted loop insertion in the upper half of the A-sheet, accounting for the increased in serum dnTBG and reduced T4 binding.

Transthyretin (TTR) Defects

Sequencing of the TTR gene, formerly known as thyroxine-binding prealbumin (TBPA) on chromosome 18 (18q11.2-q12.1), has uncovered mutations that produce variant TTR molecules with or without alterations in the binding affinity for iodothyronines (2, 67). Only those known to affect iodothyronine binding are listed in table 2 . Some of the TTR variants are responsible for the dominantly inherited familial amyloidotic polyneuropathy (FAP) , causing multiple organ failure and death in early adulthood.(67). Because TTR has a relatively lower affinity for T4 (about 100-fold lesser than that of TBG), it plays a minor role in thyroid hormone transport in blood. Accordingly, changes in the TTR concentration in serum and variant TTRs with reduced affinity for T4 have little effect on the concentration of serum T4 (68, 80). Only variant TTRs with a substantially increased affinity for iodothyronines produce significant elevation in serum T4 and rT3 concentrations and account for 2% of subjects with euthyroid hyperthyroxinemia (79).

Table 2. TTR variants with altered affinity for T 4 and potentially an effect on tests of thyroid function in serum
<0.1 0.17 – 0.41 N 30 Val – Met (68, 69)
0.54 58 Leu – His (69)
0.45 77 Ser – Tyr (69)
0.19 – 0.46 N 84 Ile – Ser (68, 69)
~1.0 0.44 122 Val – Ile (69)
3.5 N 6 Gly – Ser (70-72)
8.3-9.8 3.2 – 4.1 N 109 Ala – Thr (69, 73-75)
7.3 N 109 Ala – Val (74)
1 – 2.1 + or N 119 Thr – Met (76-79)
* HOMO, homozygous; HETERO, heterozygous.Probably overestimated since the subjects harboring this TTR variant have normal serum TT 4 concentrations.‡ Affinity of recombinant TTR Thr 109is 9-fold that of the normal TTR {Rosen, 1994 #1731}.Variant TTR tested and shown not to have altered affinity to T 4 are: Ala 60, (hetero) {Refetoff, 1986 #199; Rosen, 1993 #1604}.N, normal; + , increased

Endonucleases useful in the identification of TTR variants: Msp I -ve for Ser 6 in exon 2 associated PHA; BsoFI -ve and Fnu 4H +ve for Thr 109 ; BsoFI -ve for Val 109 and Nco I +ve for Met 119 , all in exon 4.

A family with elevated total T4 concentration which was predominantly bound to TTR was first described in 1982 by Moses et al (81). The inheritance was autosomal dominant and affected members were clinically euthyroid with normal free T4 levels measured by equilibrium dialysis. The variant TTR has a single nucleotide substitution replacing the normal Ala109 with a Thr which increases its affinity for T4, rT3 and tetraiodothyroacetic acid and to a lesser extend T3 and triiodothyroacetic acid (73, 75). Crystallographic analysis of this variant TTR revealed an alteration in the size of the T4-binding pocket (82). Another TTR gene mutation involving the same codon has been more subsequently described (74). This mutant TTR with Val109 has an increased affinity for T4 that is of similar magnitude as TTR Thr109, about 10-fold higher than that of wild-type TTR.

A more common defect found in subjects with prealbumin associated hyperthyroxinemia (PHA) is a point mutation in exon 4 of the TTR gene replacing the normal Thr119 with Met (79). First described in a single individual with normal serum total and free T4 levels (78), the majority of subsequently identified heterozygous subjects harboring the TTR Met119 had an increase in the fraction of T4 and rT3 associated with TTR, but only few had serum T4 levels above the upper limit of normal. Furthermore, their hyperthyroxinemia appears to be transient, usually in association with non-thyroidal illness (79). The variant TTRs associated with PHA are not amyloidogenic.

Variant TTRs without Known Biological Effects: Several TTR variants have been found that do not alter the properties of the molecule, nor cause FAP, and are thus of no clinical significance. Of interest is a TTR variant found in the rhesus monkey, Macaca mulatta, but not in man (83, 84)[. This variant has a slower electrophoretic mobility resulting in three phenotypes which exhibit: (a) a single rapidly migrating band similar to that found in human and other primates (PAFF); (b) a single slowly migrating band cathodal to albumin (PASS); and (c) a five banded form corresponding to the various tetrameric recombinants present in the heterozygous state possessing the two different subunits (PAFS). This finding was important because the variant rhesus PA-S could be hybridized in vitro with human TTR yielding a five-banded pattern hence, demonstrating that human TTR is also a tetramer. All naturally occurring and hybrid polymorphic variants show no detectable alteration in the binding of either T4 or retinol binding protein (85).

Human Serum Albumin (HSA) Defects

Another form of dominantly inherited euthyroid hyperthyroxinemia, later to be linked to the albumin gene on chromosome 4 (4q11-q13), was first described in 1979 (86, 87). Known as familial dysalbuminemic hyperthyroxinemia (FDH) (88), it is the most common cause of inherited increase in total T4 in serum in the Caucasian population, producing on the average a 2-fold increase in the serum total T4 concentration. In a study of 430 subjects suspected of having euthyroid hyperthyroxinemia 12% were proven to have FDH (79). The prevalence varies from 0.01 to 1.8%, depending on the ethnic origin, with the highest prevalence in Hispanics (89-92). This form of FDH has not been reported in subjects of African origin and the isolated occurrence in an Chinese (93) was possibly brought by Hispanic travelers (see below). The euthyroid status of subjects with FDH has been confirmed by normal TSH response to TRH, normal free T4 concentration measured by equilibrium dialysis using appropriate buffer systems, normal T4 production rate and normal serum sex hormone-binding globulin concentration (86, 88, 94, 95). Nevertheless, the falsely elevated free T4 values, when estimated by standard clinical laboratory techniques, has often resulted in inappropriate thyroid gland ablative or drug therapy (96-98). A recent survey of commonly used commercial tests for measurement of free T4 indicates that equilibrium or symmetric dialysis are the only tests that will consistently provide accurate values in subjects with FDH (99).

FDH is suspected when serum total T4 concentration is increased without proportional elevation in total T3 level and non suppressed serum TSH. Half of affected subjects have also rT3 values above the normal range (100) ( Table 3 ). Since the same combination of test results are found in subjects with the Thr109 TTR variant, the diagnosis of FDH should be confirmed by the demonstration that an increased proportion of the total serum T4 migrates with HSA on non denaturing electrophoresis or precipitates with anti-HSA serum.

Table 3. HSA variants with increased affinities for iodothyronines, their effect on the serum concentrations of, and affinities to these hormones
T 4 µg/dl T 3 ng/dl RT 3 ng/dl T 4 T 3
(fold the normal mean) (fold of normal mean)
R218H 16.0 (2) 147 (1.2) 29 (1.4) 10 – 15 4
R218P 146 (18.2) 253 (2.3) 135 (6.1) 11-13* 1.1*
L66P 8.7 (1.1) 320 (3.3) 22.3 (1) 1.5 40
Determined at saturation. Affinities are higher at the concentrations of T 4 and T 3 found in serum

A tight linkage between FDH and the HSA gene (lod score 5.25) was found in a large Swiss-Amish family using two polymorphic markers (100). This was followed by the identification of a missense mutation in codon 218 of the HSA gene replacing the normal arginine with a histidine (R218H) (101, 102). Furthermore, the same mutation was present in all subjects with FDH from 11 unrelated families. Its association with a Sac I+ polymorphism, suggest a founder effect and is compatible with ethnic predilection of FDH.(102) The coexistence of FDH and a TTR variant with increased affinity for T4 in the same individual (71, 72) and FDH with TBG-PD in another (103) have been reported. In both instances these individuals were the product of parents each heterozygous for of one of the two defects.

Another mutation in codon 218 with increased affinity to iodothyronines was first identified by Wada et al (9). The mutation, a replacement of the normal Arg218 with a Pro (R218P), initially believed to be unique for Japanese was also identified in a Swiss family with no Asian ancestry ( Fig. 4 ) (10). In this form of FDH, serum total T4 levels are 14-20-fold the normal mean, a level confirmed by measurements in serum extracts by HPLC. Total rT3 and T3 concentrations are 7- and 2-fold above the mean, respectively. Thus, in order 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 Kas measured at saturation were similar, 5.4 x 106 M-1 and 6.4 x 106 M-1 for HSA R218H, respectively (10, 104, 105) ( Table 3 ). However, at T4 concentrations equivalent to those found in subjects with HSA R218P, the dialysable FT4 concentration was 11-fold higher in serum of subjects with HSA R218H and 49-fold higher in serum with the common type HSA only (10).

Figure 4. A Swiss family with HSA R218P: genotyping, pedigree and thyroid function tests. <b>A,</b> Genotyping for the mutation HSA R218P. Results are aligned with each subject depicted on the pedigree in B. Amplification of a segment of the HSA gene containing the mutation with a mismatched oligonucleotide primer creates a new restriction site for Ava II only in the presence of the mutant nucleotide (CGC -> C <b>C</b> C). Affected subjects expressing proline 218 (C <b>C</b> C) show a 122 bp DNA fragment produced by enzymatic digestion of the mutant allele. Note that all affected subjects are heterozygous and that the 153 bp fragment amplified from DNA of the two normal subjects, expressing arginine 218 (CGC) only, resists enzymatic digestion. <b>B,</b> Pedigree of the family. Roman numerals indicate each generation and numbers below each symbol identify the subject. Individuals expressing the FDH phenotype are indicated by half filled symbols. <b>C,</b> Thyroid function tests. Results are aligned with each symbol. Values outside the normal range are in bold numbers. Note the disproportionate increase in serum T4 concentration as compared to that of T3 in the affected individuals. Subject I-1, a year old man, had diabetes mellitus with multiple organ complications and mild subclinical hypothyroidism, explaining the relatively lower serum T4 and T3 but not rT3 levels. Adapted from Pannain et al (10).

A third mutation, a replacement of the normal Leu66 with a Pro (L66P) has been identified in a single Thai family (3). It produces a 40-fold increase in the affinity for T3 but only 1.5-fold increase in the affinity for T4 ( Table 3 ). As a consequence, patients have hypertriiodothyroninemia but not hyperthyroxinemia. In this FDH-T3, serum T3 concentrations are falsely low, or even undetectable, when T3 is measured using an analog of T3 as a tracer rather than a radioisotope. It has resulted in the inappropriate treatment with thyroid hormone (3).

Bisalbuminemia and Analbuminemia: Variant albumins, with altered electrophoretic mobility produce “bisalbuminemia” in the heterozygotes (106). T4 binding has been studied in subjects from unrelated families with a slow HSA variant. In two studies only the slow moving HSA bound T4 (107, 108) and in another, both (109). The differential binding of T4 to one of the components of bisalbumin may be due to enhanced binding to the variant component with charged amino acid sequence. Bisalbuminemia does not seem to be associated with gross alterations in thyroid hormone concentration in serum.

Analbuminemia is extremely rare, occurring in less than 1 in a million individuals (110). The first case was reported in 1954 (111) but the HSA gene mutation was identified 56 years later (112). The less than 50 cases so far reported have nonsense mutations causing premature termination of translation or splicing defects (113). Despite the complete lack of such an important substance, symptoms are remarkably mild owing to the a compensation by an increase in non-albumin serum proteins. Studies with respect to T4-transport showed no clear effect or slight increase total serum iodothyronines, associated with increased levels of TBG and TTR. (113, 114). The latter two normalized when serum HSA was restored to normal by multiple transfusions (114).


Supported in part by grants DK-15070, DK020595 and RR-04999 from the National Institutes of Health (USA).


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