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Dysprealbuminemic hyperthyroxinemia in a patient with hyperthyroid graves disease.

The vast preponderance of circulating thyroid hormones are bound to 3 classes of plasma proteins: thyroxine-binding globulin (TBG) [3] transthyretin (TTR; also termed thyroxine-binding prealbumin), and albumin (1). However, only the small unbound or free fractions of circulating thyroxine ([T.sub.4]) and triiodothyronine ([T.sub.3]), 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), [T.sub.4] and/or [T.sub.3] (2). In this circumstance, the serum free [T.sub.4] and [T.sub.3] 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 [T.sub.4] binding studies may confirm it (6).

Abnormal [T.sub.4] binding to [T.sub.4] -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 [T.sub.4] binding affinity. The trait was inherited in an autosomaldominant manner and attributed to a mutation in exon 4 of the TTR gene. This mutation encodes a single threo-nine-to-alanine mutation in the mature TTR protein (8) and increases the [T.sub.4] binding affinity of the molecule 3-fold (9). Additional families with other mutations have subsequently been characterized (10-12). An increase in [T.sub.4] 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.

Case Report

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 [T.sub.4] (156 [micro]g/L). A [sup.123]I 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 [sup.131]I in January 2003. Four weeks later, her serum free [T.sub.4] was 32 ng/L with an undetectable serum TSH (Fig. 1). In mid-February, which was 6 weeks after radioiodine therapy, her serum free [T.sub.4] 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 [T.sub.3], 1.6 [micro]g/L (reference interval, 0.8-2.0 [micro]g/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 [T.sub.4] remained mildly low, at 4.8 ng/L. She was then asymptomatic, but treatment with 0.05 mg/day [T.sub.4] was begun. By late April, 16 weeks after treatment with radioiodine and while she was on low-dose [T.sub.4] therapy, her free [T.sub.4] 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 [T.sub.4] dose was increased to 0.1 mg/day, and 4 weeks later, in late May, her serum free [T.sub.4] 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 [T.sub.4] 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 [T.sub.4] 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 [T.sub.4] was then frankly increased (20 ng/L). This pattern of normal serum TSH and euthyroid clinical status with an increased serum free [T.sub.4] continued (Fig. 1).

[FIGURE 1 OMITTED]

Among the patient's family members, only her father was available for testing; his serum free [T.sub.4] concentration was within the reference interval (13 ng/L). Additional studies to assess the patient's thyroid status were performed.

Additional Laboratory Studies

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 [T.sub.4] with an increased free [T.sub.4] by immunoassay and a normal serum TSH, the patient's serum free [T.sub.4] 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 [T.sub.4] -binding protein panel was performed at the Nichols Institute (6). This assay assesses the proportion of [sup.125]I-labeled [T.sub.4] bound to TBG, albumin, and TTR, with slight modification from the originally reported assay (15) by the following methodology. Exogenous [sup.125]I-[T.sub.4] (3.3 [micro]Ci; 10 [micro]L) was incubated with 100 [micro]L of the patient's serum at 37[degrees]C for 30 min, after which the incubation was terminated by chilling at 1[degrees]C. Serum (1 [micro]L 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 [T.sub.4] , of each fragment was quantified in a gamma counter and compared with exogenous binding protein calibrators. An abnormally high fraction of [sup.125]I-[T.sub.4] was bound to the patient's serum TTR fraction, and the patient's [T.sub.4] :TTR ratio was increased. The TBG- and albumin-bound fractions were within their respective reference intervals. In addition, from the reported radioactive peaks, no [T.sub.4] -bound IgG was present, excluding the possibility of [T.sub.4] autoantibodies (16) (Fig. 2 and Table 1). These findings confirmed the diagnosis of dysprealbuminemic hyperthyroxinemia.

[FIGURE 2 OMITTED]

Discussion

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 [T.sub.4] (17). When the serum concentrations of the [T.sub.4] binding proteins, TBG, albumin, and TTR, are normal but the [T.sub.4] concentration still appears increased in apparently euthyroid individuals, genetic mutations in other [T.sub.4] -binding proteins may be the cause. Mutations in the genes encoding the [T.sub.4] -binding subspecies of albumin (4) or TTR can lead to significantly increased [T.sub.4] binding affinity and an increased serum total [T.sub.4] concentration. Many widely used free [T.sub.4] immunoassays use a thyroid hormone analog tracer, which does not bind to TBG and consequently competes only with nonTBG-bound [T.sub.4] , which is a reasonable estimate of the free [T.sub.4] in most circumstances. However, if the analog, such as endogenous [T.sub.4] , binds to a mutant albumin or TTR with increased binding affinity, then the calculated free [T.sub.4] will also appear increased. Measurement of the serum [T.sub.4] after equilibrium dialysis is the most accurate method to remove potential [T.sub.4] -binding protein interferences (18), although a report by Hoshikawa et al. (19) demonstrated that even this assay may provide falsely increased [T.sub.4] results.

Several mutations in the TTR protein have been reported to lead to enhanced TTR binding affinity for [T.sub.4] . For example, an alanine-to-threonine mutation at position 109 of TTR causes a 3-fold increase in [T.sub.4] 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 [T.sub.4] 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 [T.sub.4] and free [T.sub.4] . 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 [T.sub.4] by equilibrium dialysis followed by evidence of increased [T.sub.4] 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 [T.sub.4] slowed the restoration of euthyroidism with a full t-[T.sub.4] 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 [T.sub.4] -binding protein panel showing increased TTR fraction [T.sub.4] 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.

We thank Dr. Raj Pandian from the Nichols Institute for helpful discussions regarding the [T.sub.4] binding protein analysis. We also thank Dr. William Clarke for helpful comments on analytical methodology.

References

(1.) Werner SC, Ingbar SH, Braverman LE, Utiger RD. Werner and Ingbar's the thyroid: a fundamental and clinical text, 7th ed. Philadelphia: Lippincott Raven, 1996:96-110.

(2.) Kvetny J. Nuclear binding and cellular metabolism of thyroxine in a euthyroid patient with hyperthyroxinaemia. Clin Endocrinol (Oxf) 1983;18:251-7.

(3.) Borst GC, Eil C, Burman KID. Euthyroid hyperthyroxinemia. Ann Intern Med 1983;98:366-78.

(4.) Ruiz M, Rajatanavin R, Young RA, Taylor C, Brown R, Braverman LE, et al. Familial dysalbuminemic hyperthyroxinemia: a syndrome that can be confused with thyrotoxicosis. N Engl J Med 1982;306: 635-9.

(5.) Refetoff S, Marinov VS, Tunca H, Byrne MM, Sunthornthepvarakul T, Weiss RE. A new family with hyperthyroxinemia caused by transthyretin Val109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone-a clinical research center study. J Clin Endocrinol Metab 1996;81:3335-40.

(6.) Pandian MR, Morgan C, Nelson JC, Fisher DA. Differentiating various abnormalities of thyroxin binding to serum proteins by radioelectrophoresis of thyroxin and immunoassay of binding proteins. Clin Chem 1990;36:457-61.

(7.) Moses AC, Lawlor J, Haddow J, Jackson IM. Familial euthyroid hyperthyroxinemia resulting from increased thyroxine binding to thyroxine-binding prealbumin. N Engl J Med 1982;306:966-9.

(8.) Moses AC, Rosen HN, Moller DE, Tsuzaki S, Haddow JE, Lawlor J, et al. A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia. J Clin Invest 1990;86:2025-33.

(9.) Rosen HN, Murrell JR, Liepnieks JJ, Benson MD, Cody V, Moses AC. Threonine for alanine substitution at position 109 of transthyretin differentially alters human transthyretin's affinity for iodothyronines. Endocrinology 1994;134:27-34.

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(13.) Maye P, Bisetti A, Burger A, Docter R, Gaillard R, Griessen M, et al. Hyperprealbuminemia, euthyroid hyperthyroxinemia, ZollingerEllison-like syndrome and hypercorticism in a pancreatic endocrine tumour. Acta Endocrinol (Copenh) 1989;120:87-91.

(14.) Alexopoulos A, Hutchinson W, Bari A, Keating JJ, Johnson PJ, Williams R. Hyperthyroxinaemia in hepatocellular carcinoma: relation to thyroid binding globulin in the clinical and preclinical stages of the disease. Br J Cancer 1988;57:313-6.

(15.) George PM, Sheat JM, Palmer BN. Detection of protein binding abnormalities in euthyroid hyperthyroxinemia. Clin Chem 1988; 34:1745-8.

(16.) Bhagat CI, Garcia-Webb P, Watson F, Beilby JP. Interference in radioimmunoassay of total serum thyroxin and free thyroxin due to thyroxin-binding autoantibodies. Clin Chem 1983;29:1324-5.

(17.) Cousin P, Dechaud H, Grenot C, Lejeune H, Pugeat M. Human variant sex hormone-binding globulin (SHBG) with an additional carbohydrate chain has a reduced clearance rate in rabbit. J Clin Endocrinol Metab 1998;83:235-40.

(18.) Bartalena L, Bogazzi F, Brogioni S, Burelli A, Scarcello G, Martino E. Measurement of serum free thyroid hormone concentrations: an essential tool for the diagnosis of thyroid dysfunction. Horm Res 1996;45:142-7.

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(20.) Izumoto S, Kornberg J, Herbert J. Two transthyretin mutations associated with euthyroid hyperthyroxinemia. J Rheumatol 1993; 20:186.

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SCOTT J. CAMERON, [1] JUDITH C. HAGEDORN [2] LORI J. SOKOLL, [1] PATRIZIO CATUREGLI [2] and PAUL W. LADENSON [1,2] *

[1] Clinical Chemistry Division, Department of Pathology, and [2] Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD.

[3] Nonstandard abbreviations: TBG, thyroid-binding globulin; TTR, transthyretin; [T.sub.4] , thyroxine; [T.sub.3] , triiodothyronine; and TSH, thyroid-stimulating hormone.

* Address 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@jhmi.edu.

Received March 3, 2005; accepted March 25, 2005.

Previously published online at DOI: 10.1373/clinchem.2005.050518
Table 1. Amount of [sup.125]I-[T.sub.4] bound to TBG,
albumin, and TTR. (a)

 [sup.125]I-[T.sub.4]
 bound to plasma
 protein Plasma protein

TBG 72 [micro]g/L (36-84) 21 mg/L (17-36)
Albumin 8 [micro]g/L (5-12) 42 g/L (37-51)
TTR 36 [micro]g/L (2-20) 240 mg/L (170-340)

 Bound [T.sub.4]:plasma
 protein ratio

TBG 3.4 [micro]g/mg (1.9-3.5)
Albumin 0.19 [micro]g/g (0.11-0.28)
TTR 0.15# [micro]g/mg (0.02-0.07)

(a) Binding of exogenously added radioactive [T.sub.4] to serum
TBG, albumin, and TTR (prealbumin) was quantified after
electrophoretic separation and confirmation of each protein. TBG,
albumin, and TTR were also quantified to provide a proportionate
[T.sub.4] binding:protein ratio. Values in parentheses are the
reference intervals. Abnormal values are shown in bold. Total serum
[T.sub.4] was quantified in the same sample and was within the
reference interval, at 116 [micro]g/L (reference interval, 56-137
[micro]g/L).

Note: Abnormal values are shown in bold indicated with #.
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Title Annotation:Case Report
Author:Cameron, Scott J.; Hagedorn, Judith C.; Sokoll, Lori J.; Caturegli, Patrizio; Ladenson, Paul W.
Publication:Clinical Chemistry
Date:Jun 1, 2005
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