Clinical Chemistry 51: 1065-1069, 2005.
First published April 15, 2005; 10.1373/clinchem.2005.050518
(Clinical Chemistry. 2005;51:1065-1069.)
© 2005 American Association for Clinical Chemistry, Inc.
Dysprealbuminemic Hyperthyroxinemia in a Patient with Hyperthyroid Graves Disease
Scott J. Cameron1,
Judith C. Hagedorn2,
Lori J. Sokoll1,
Patrizio Caturegli2 and
Paul W. Ladenson1,2,a
1 Clinical Chemistry Division, Department of Pathology, and 2
Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD.
aAddress correspondence to this author at: Johns Hopkins Medical Institutions, 1830 E. Monument St., Suite 333, Baltimore, MD 21287-0003. Fax 410-955-3916; e-mail ladenson{at}jhmi.edu.
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Abstract
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Rare mutant forms of circulating albumin and prealbumin [transthyretin (TTR)] have increased binding affinity for thyroxine (T4). Patients with these variant plasma proteins, as a result of inherited mutations or as a paraneoplastic phenomenon, typically present with increased serum total T4 and, by some assay methodologies, an increased free T4 as well. Although these individuals are, in fact, euthyroid, nonspecific symptoms may lead to inappropriate treatment for hyperthyroidism. We present a 34-year-old woman in whom a mutant form of TTR with increased T4 binding affinity and coexisting Graves disease was present. Subsequent 131I therapy led to development of postablative hypothyroidism, which was obscured by her higher serum free T4 concentration. Circulating thyroid-binding globulin (TBG), albumin, and TTR concentrations were all within their respective reference limits. A T4-binding protein panel confirmed that TTR-bound T4 was significantly increased, whereas TBG- and albumin-bound T4 was normal, indicating that this patient had euthyroid dysprealbuminemic hyperthyroxinemia, which had been masked by the initial presentation of hyperthyroidism. These findings indicate that hypothyroidism can be masked by coexisting euthyroid dysprealbuminemic hyperthyroxinemia.
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Introduction
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The vast preponderance of circulating thyroid hormones are bound to 3 classes of plasma proteins: thyroxine-binding globulin (TBG),
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transthyretin (TTR; also termed thyroxine-binding prealbumin), and albumin (1). However, only the small unbound or free fractions of circulating thyroxine (T4) and triiodothyronine (T3), 0.03% and 0.3%, respectively, enter cells in target tissues to affect thyroid hormone actions. An increase in the plasma concentration or in the thyroid hormone binding affinity of any one of these proteins can lead to higher serum concentrations of total, but not free (unbound), T4 and/or T3 (2). In this circumstance, the serum free T4 and T3 concentrations, as determined by equilibrium dialysis, usually remain within reference values, as does the serum TSH concentration. Individuals with one of these conditions causing euthyroid hyperthyroxinemia (3) and/or hypertriiodothyroninemia may be misdiagnosed and even treated as having thyrotoxicosis (4)(5). Recognition of a nonsuppressed serum thyroid-stimulating hormone (TSH) concentration should raise suspicion of the disorder, and in vitro T4 binding studies may confirm it (6).
Abnormal T4 binding to T4-binding prealbumin (TTR) is a rare cause of euthyroid hyperthyroxinemia. Moses et al. (7) first described familial euthyroid hyperthyroxinemia attributable to a mutant TTR with increased T4 binding affinity. The trait was inherited in an autosomal-dominant manner and attributed to a mutation in exon 4 of the TTR gene. This mutation encodes a single threonine-to-alanine mutation in the mature TTR protein (8) and increases the T4 binding affinity of the molecule 3-fold (9). Additional families with other mutations have subsequently been characterized (10)(11)(12). An increase in T4 binding by TTR has also been reported as an acquired paraneoplastic phenomenon in patients with pancreatic and hepatic tumors (13)(14). Here we describe a patient with typical hyperthyroid Graves disease in whom coexistence of euthyroid dysprealbuminemic hyperthyroxinemia masked the emergence and complicated the management of postablative hypothyroidism.
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Case Report
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A 34-year-old mother of a 2-year-old was referred to the Endocrinology Consultation Service at the Johns Hopkins Medical Institutions in December 2002 for evaluation and management of thyrotoxicosis. Over the preceding 2 months, the patient had experienced a 4.5-kg weight loss despite increased appetite, mild heat intolerance, palpitations, an increase in her long-standing hand tremor, intermittent anxiety, hyperdefecation, and light menstrual flow. Over the past year, she had also been unable to become pregnant again. The patient had experienced no local neck or ophthalmologic symptoms. Her past medical history was remarkable only for a benign essential tremor, and she was taking no medications. The patient’s paternal grandmother had undergone thyroid surgery for an unknown disorder; there was no other history of thyroid disease or abnormal thyroid function tests in her parents, 3 siblings, or son. Her mother died of complications from multiple sclerosis.
On physical examination, the patient was a tense woman who weighed 42.5 kg and was 1.65 m tall; her pulse was 100 beats/min and regular, and her blood pressure was 100/60 mmHg. She had bilateral lid lag and borderline proptosis (Hertel exophthalmometry: OD, 22 mm, OS, 21 mm, IPD, 94 mm); there was no limitation of extraocular gaze or periorbital edema. Her thyroid gland was twice the normal size (40 gm), symmetrical without a palpable pyramidal lobe, smooth, rubbery, and nontender with no bruit. Her cardiac, pulmonary, and abdominal examinations were normal. She had bilateral coarse hand tremor, but no edema or proximal muscle atrophy or weakness.
Previous laboratory tests included an undetectable serum TSH concentration (<0.02 mIU/L) and increased serum total T4 (156 µg/L). A 123I fractional thyroid uptake and scan had shown 43% uptake at 24 h and a symmetrically enlarged thyroid gland with homogeneous tracer distribution.
The patient was advised to receive and accepted radioiodine therapy. She was given 14.7 mCi of 131I in January 2003. Four weeks later, her serum free T4 was 32 ng/L with an undetectable serum TSH (Fig. 1
). In mid-February, which was 6 weeks after radioiodine therapy, her serum free T4 concentration had decreased to just above the upper limit of the reference interval (18 ng/L; reference interval, 6–16 ng/L; Tosoh Bioscience, Inc.), with a high-normal serum T3, 1.6 µg/L (reference interval, 0.8–2.0 µg/L; Tosoh Bioscience) and persistently undetectable serum TSH (<0.02 mIU/L; reference interval, 0.5–4.5 mIU/L; Tosoh Bioscience). By mid-March, 9 weeks after radioiodine therapy, the patient’s serum TSH had become increased to 20 mIU/L, but her serum free T4 remained mildly low, at 4.8 ng/L. She was then asymptomatic, but treatment with 0.05 mg/day T4 was begun. By late April, 16 weeks after treatment with radioiodine and while she was on low-dose T4 therapy, her free T4 concentration was in the lower half of the reference interval, 8 ng/L, but she had persistent markedly increased serum TSH, 66 mIU/L. The patient had then gained weight despite poor appetite and was experiencing fatigue, dry skin, muscle cramps, and mental and emotional detachment. On examination, she had gained 3 kg and had no palpable thyroid tissue, slowing of her ankle reflex relaxation phase, and disappearance of her preexisting hand tremor. Her T4 dose was increased to 0.1 mg/day, and 4 weeks later, in late May, her serum free T4 was at the upper limit of the reference interval, 16 ng/L, in association with mild but persistently increased TSH, 9.8 mIU/L. This constellation of mildly increased free T4 in association with still increased TSH was still present by mid-June, during which time she had persistent fatigue, slowed mentation, and depressed mood. Her T4 dose was then increased to 0.112 mg/day. One month later, in July, her serum TSH had returned to within reference values (1.9 mIU/L), and her symptoms had disappeared, but her free T4 was then frankly increased (20 ng/L). This pattern of normal serum TSH and euthyroid clinical status with an increased serum free T4 continued (Fig. 1
).
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Figure 1. Serum free T4 and TSH concentrations after treatment for Graves disease.
(A), free T4 (ng/L) was measured by competitive immunoassay over a 10-month time span after treatment with a single dose of 131I (arrowhead). After postablative hypothyroidism, an oral synthroid (L-T4) regimen was initiated (daily doses and treatment period are noted below the graph). The reference interval for free (unbound) T4 is 6–16 ng/L (dashed lines). (B), parallel measurements of serum high-sensitivity TSH (mIU/L) by immunoenzymatic assay over a 6-month time period. The reference interval is 0.5–4.5 mIU/L (dashed lines).
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Among the patient’s family members, only her father was available for testing; his serum free T4 concentration was within the reference interval (13 ng/L). Additional studies to assess the patient’s thyroid status were performed.
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Additional Laboratory Studies
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Further laboratory analyses involving the patient and her father were performed with approval by the Johns Hopkins Institutional Review Board and after informed consent. During the period when the patient was taking 0.112 mg/day T4 with an increased free T4 by immunoassay and a normal serum TSH, the patient’s serum free T4 was assessed by RIA of the dialysate after equilibrium dialysis and was found to be normal (22 ng/L; reference interval, 8–27 ng/L; Nichols Institute). The serum TBG concentration measured on 2 occasions was within reference values (24 and 21 mg/L; reference interval, 8–27 mg/L) by RIA (Nichols Institute). The serum TTR (240 mg/L; reference interval, 170–340 mg/L) and albumin (42 g/L; reference interval, 37–51 g/L) were within their respective reference intervals, as assessed by rate nephelometry (Nichols Institute).
A T4-binding protein panel was performed at the Nichols Institute (6). This assay assesses the proportion of 125I-labeled T4 bound to TBG, albumin, and TTR, with slight modification from the originally reported assay (15) by the following methodology. Exogenous 125I-T4 (3.3 µCi; 10 µL) was incubated with 100 µL of the patient’s serum at 37 °C for 30 min, after which the incubation was terminated by chilling at 1 °C. Serum (1 µL with bromphenol blue added as a visual marker) was separated by electrophoresis (12 g/L agarose, pH 8.7, with 40 mmol/L sodium borate buffer containing 1 mmol/L calcium lactate) in a vertical electrophoresis unit with an applied current of 20 mA for 2.5 h. The separated protein gel was dried for 1 h under a 500-W lamp. The dried gel was sliced into 3-mm fragments, and the radioactivity, representing bound T4, of each fragment was quantified in a gamma counter and compared with exogenous binding protein calibrators. An abnormally high fraction of 125I-T4 was bound to the patient’s serum TTR fraction, and the patient’s T4:TTR ratio was increased. The TBG- and albumin-bound fractions were within their respective reference intervals. In addition, from the reported radioactive peaks, no T4-bound IgG was present, excluding the possibility of T4 autoantibodies (16) (Fig. 2
and Table 1
). These findings confirmed the diagnosis of dysprealbuminemic hyperthyroxinemia.
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Figure 2. T4-binding protein analysis.
After incubation of the patient’s serum with 125I-labeled T4 (see text), the serum was separated by electrophoresis and peak areas for TBG, albumin, TTR (prealbumin), and IgG ( -globulin) were quantified. The peak intensity for each radiolabeled fraction is reported as a function of anodal migration. The TBG:TTR peak ratio is usually  3:1, but is closer to 2:1 in this patient.
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Discussion
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Euthyroid dysprealbuminemic hyperthyroxinemia is a rare disorder, which in this patient was coincident with hyperthyroid Graves disease. Hyperthyroxinemia in euthyroid patients is most commonly caused by the presence of altered hepatic TBG synthesis, with increased glycosylation producing a decreased clearance rate and resulting higher serum concentrations of T4 (17). When the serum concentrations of the T4-binding proteins, TBG, albumin, and TTR, are normal but the T4 concentration still appears increased in apparently euthyroid individuals, genetic mutations in other T4-binding proteins may be the cause. Mutations in the genes encoding the T4-binding subspecies of albumin (4) or TTR can lead to significantly increased T4 binding affinity and an increased serum total T4 concentration. Many widely used free T4 immunoassays use a thyroid hormone analog tracer, which does not bind to TBG and consequently competes only with non-TBG–bound T4, which is a reasonable estimate of the free T4 in most circumstances. However, if the analog, such as endogenous T4, binds to a mutant albumin or TTR with increased binding affinity, then the calculated free T4 will also appear increased. Measurement of the serum T4 after equilibrium dialysis is the most accurate method to remove potential T4-binding protein interferences (18), although a report by Hoshikawa et al. (19) demonstrated that even this assay may provide falsely increased T4 results.
Several mutations in the TTR protein have been reported to lead to enhanced TTR binding affinity for T4. For example, an alanine-to-threonine mutation at position 109 of TTR causes a 3-fold increase in T4 binding affinity, which was observed in vivo (8) and confirmed by in vitro studies (9). An alanine-to-valine mutation at position 109 in TTR similarly led to euthyroid hyperthyroxinemia (20). Moreover, a threonine-to-methionine mutation in TTR at position 119 was reported to enhance T4 binding affinity 2-fold in a patient with euthyroid hyperthyroxinemia (12)(21).
The most common clinical confusion resulting from dysprealbuminemic hyperthyroxinemia is misdiagnosis of thyrotoxicosis in a patient with nonspecific clinical manifestations suggesting thyroid hormone excess in association with increased serum total T4 and free T4. Suspicion of this unusual cause of euthyroid hyperthyroxinemia is typically first aroused by a discordantly normal serum TSH concentration. Confirmation of a normal serum free T4 by equilibrium dialysis followed by evidence of increased T4 binding by the TTR plasma protein fraction established the diagnosis in this case. Although to our knowledge it has not been reported previously, dysprealbuminemic hyperthyroxinemia can also obscure the diagnosis of hypothyroidism. In patients with conventional primary hypothyroidism, the increased serum TSH concentration would provide a clue to the correct diagnosis. However, in patients with hypothyroidism without a high TSH, such as those with central hypothyroidism, the diagnosis might remain inapparent. In our patient with treated hyperthyroidism, the serum TSH suppression that is known to persist for weeks or months after reversal of thyrotoxicosis (22) temporarily obscured the diagnosis of postablative hypothyroidism. Furthermore, the inappropriately high measured free T4 slowed the restoration of euthyroidism with a full L-T4 replacement dose.
In summary, dysprealbuminemic hyperthyroxinemia is a rare inherited or paraneoplastic form of euthyroid hyperthyroxinemia that can lead to misdiagnosis of thyroid disease states. Often the discordant serum TSH concentration, along with an inconsistent clinical presentation, first suggests the diagnosis, which can then be established with a T4-binding protein panel showing increased TTR fraction T4 binding. The unusual coincidence in our patient of dysprealbuminemic hyperthyroxinemia and treated Graves disease led to a delay in accurate diagnosis and optimal treatment of hypothyroidism.
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Acknowledgments
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We thank Dr. Raj Pandian from the Nichols Institute for helpful discussions regarding the T4-binding protein analysis. We also thank Dr. William Clarke for helpful comments on analytical methodology.
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Footnotes
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1 Nonstandard abbreviations: TBG, thyroid-binding globulin; TTR, transthyretin; T4, thyroxine; T3, triiodothyronine; and TSH, thyroid-stimulating hormone. 
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Abstract
Introduction
