Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of the inherited increase of serum thyroxine in Caucasians. This disorder occurs due to a missense mutation in the human serum albumin, resulting in an increased affinity of thyroxine to the binding sites on the human serum albumin (HSA) molecule. HSA is a carrier protein of thyroid hormones and only 10% of thyroxine (T4) is bound to human serum albumin, 75% is bound to thyroxine-binding globulin, 15% to transthyretin, and 0.03% is free. The disorder is characterized by a greater elevation of serum thyroxine than triiodothyronine (T3). The high serum concentration of T4 is due to the modification of a binding site located in the N-terminal half of HSA (in subdomain IIA). Arg218 or Arg222 gets replaced with smaller amino acids, such as histidine, proline, or serine, due to missense mutation; this reduces the steric hindrances in the binding site and creates a high-affinity binding site for thyroxine. We herein report a case of FDH with a characteristically elevated total T4 and normal free T4 (measured by equilibrium dialysis).
Thyroid hormones (TH) (T3 and T4) circulate in the blood bound to the carrier proteins, i.e., thyroxine-binding globulin (TBG), transthyretin (TTR), prealbumin, and human serum albumin (HSA). Thyroxine-binding globulin, which has the highest affinity for thyroxine (T4) (Kd = 0.1 nM), binds about three-quarters of the hormone carried in the circulation; the remainder is divided more or less equally between transthyretin and HSA. Albumin binds T4 with a Kd of ≈2 μM and provides an important fast-response reservoir for the hormone during capillary transit . Extracellular T4 and T3 are protein-bound by 99.97% and 99.7%, respectively. Because free thyroid hormones exist in equilibrium with the carrier proteins, any factor that affects the quantity/quality of the carrier invariably affects the pharmacokinetics and pharmacodynamics of the thyroid hormones . This is best exemplified in familial dysalbuminemic hyperthyroxinemia (FDH), an autosomal dominant disorder characterized by an elevated total T4 (TT4), elevated free T4 (FT4), normal thyroid stimulating hormone (TSH), and T3 level, as measured by a one/two-step immunoassay. Some rare cases of elevated T3 have been described. We describe the case of a patient with FDH presenting with hyperthyroxinemia.
A 79-year-old Hispanic male with a history of hypertension, schizoaffective disorder, benign prostatic hypertrophy, and chronic renal insufficiency was admitted for evaluation of a wide complex tachycardia found on his outpatient 24-hour Holter monitor done to evaluate his complaint of frequent palpitations. The patient acknowledged that he had palpitations for several years and that he was always nervous. He also stated that this “nervousness runs in the family”. There was no associated weight loss, unusual hair loss, or visual changes. He also denied any neck mass/goiter, diarrhea, or abdominal skin rash/thickening but stated that his hand always “shakes”. He denied any chest pain or shortness of breath, either at rest or with exertion. He also denied any orthopnea or paroxysmal nocturnal dyspnea but had complained of chronic leg swelling with no recent change. Exercise tolerance remained very good and unchanged.
On admission, an endocrinology consult was requested for evaluation of persistently elevated TT4 and FT4 levels. His vital signs were stable and physical exam revealed a mildly anxious elderly male with coarse tremors of the hands on extension. The rest of the examination was unremarkable. A sonogram of the thyroid gland showed bilateral prominent lobes, the left greater than the right. A thyroid iodine (I)-123 uptake scan was 19.4% (normal level: 15 - 40%). It also showed a mildly enlarged but non-palpable lower pole of the thyroid lobe with homogenous activity throughout the gland. Thyroid function tests (TFTs) done using routine automated direct one-step/two-step immunoassays showed normal TSH levels of 1.22 and 0.78, respectively (normal level: 0.34 - 5.6 mU/mL). T3 levels were normal at 98.4 and 125.3 ng/dL (normal level: 87 - 178 ng/dL). However, TT4 and FT4 levels were elevated. FT4 levels were 2.25 and 2.34 ng/dL (normal level: 0.58 - 1.64); and TT4 levels were 17.58 and 18.69 (normal level: 6.09 - 12.2). Free T3 by equilibrium dialysis was 402 ng/dL (normal level: 230 - 420) and an alpha subunit for pituitary hormone was less than 0.3 ng/ml (normal level: < 1.0). Free T4 by equilibrium dialysis was normal at 2.1 ng/dl (normal level: 0.8 - 2.7).
Cardiac workup, including echocardiogram, cardiac enzymes, stress test, and telemetry monitoring, was unremarkable. He was treated with a beta-blocker and discharged after being assured that his thyroid condition was benign.
Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant inherited disorder identified in 1979 independently by Henneman et al.  and Lee et al. , and it was not until 1994 that Petersen  and Sunthornthepvarakul , independent of each other, identified the precise genetic defect. FDH is characterized by a missense mutation in the human serum albumin, which is a protein synthesized by the liver. Of the several iodothyronine-binding sites on the HSA molecule, only one has a relatively high affinity for T4 and T3. A mutation on this binding site leads to higher concentration of thyroid hormone in the bloodstream. The mutation involves codon 218, which is normally arginine, and it gets replaced with histidine, proline, or serine (or codon 222), which is also arginine that gets replaced with isoleucine. These mutations in the codon 218 and codon 222 for a smaller amino acid reduces the steric hindrances and creates a high-affinity binding site for T4 [2, 9]. Individuals with FDH are heterozygous for the mutation. Although they may present with altered thyroid hormone levels, they are clinically euthyroid.
Table 1 describes the various albumin variants, the mutations causing these variants, its prevalence, and also the factors by which the concentration of thyroid hormones are increased.
Our case report and TFT results fit the classic description of FDH, an autosomal dominant disorder characterized by an elevated TT4, elevated FT4 (as measured by one-step/two-step immunoassay but normal by equilibrium dialysis), a normal or rarely elevated T3, and normal TSH. The estimated prevalence of FDH among the Caucasian population is 1 in 10,000 individuals, and it is much higher in subjects of Hispanic origin, i.e., 1.0 - 1.8% .
The initial total and free T4 assays were performed using the labeled antibody method. This is the common method of choice for initial testing in most centers due to the wide availability and low cost. To confirm or better delineate an abnormal result, direct equilibrium dialysis is the next test of choice, as it was in our patient. While this method has a better ability to accurately report true free T4 values in the face of confounding variables, false-positives may still occur . Hoshikawa et al. have reported false-positive results of elevated free T4 assays using equilibrium dialysis/radioimmunoassay (RIA), and they suggest that this assay is not an ultimate standard for diagnosing FDH, especially in patients with the R218P mutation of the ALB gene . They further recommended ultrafiltration as an added measure to increase the accuracy of testing prior to RIA.
On review of the literature, we found the following studies and case reports (shown in Table 2) regarding familial dysalbuminemic hyperthyroxinemia.
Some of the important differential diagnoses that need to be considered as well include TSH-secreting pituitary adenoma, a rare condition accounting for 2% of all pituitary adenomas, which is characterized by elevated/normal serum TSH and elevated TH levels with high alpha subunit. The patient is usually thyrotoxic, and magnetic resonance imaging (MRI) usually shows a pituitary tumor/hyperplasia . Thyroid hormone resistance syndrome is another important differential, characterized clinically by goiter, sinus tachycardia, and elevated/normal serum levels of TSH and elevated thyroid hormones: thyroxine (T4) and triiodothyronine (T3). It is rare and inherited in an autosomal dominant fashion. The primary defect in a thyroid hormone-resistant syndrome patient is usually a mutation involving the thyroid hormone receptor beta, and recently, mutations in the thyroid hormone receptor alpha gene have been identified which are associated with near-normal thyroid hormone levels with hypothyroid features . Therefore, a high clinical suspicion of FDH is required in evaluating euthyroid patients with elevated total T4 and normal FT4 levels. In order to avoid unwanted treatment of euthyroid persons with hyperthyroxinemia or hypertriiodothyroninemia, protein sequencing and/or sequencing of the albumin gene should be performed.
Familial dysalbuminemic hyperthyroxinemia is usually benign and does not usually require treatment unless there is a concurrent different thyroid dysfunction. Because of the paucity of knowledge of this condition, particularly among non-endocrinologists, there is a tendency for inappropriate treatment, including radioactive iodine, medications, and thyroid surgery and hence, the need for extensive education on this condition.
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Effect of Albumin Polymorphism on Thyroid Hormones: A Case Report and Literature Review
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Cite this article as:
Mahendhar R, Shahbaz A, Riaz M, et al. (July 01, 2018) Effect of Albumin Polymorphism on Thyroid Hormones: A Case Report and Literature Review. Cureus 10(7): e2903. doi:10.7759/cureus.2903
Received by Cureus: June 07, 2018
Peer review began: June 07, 2018
Peer review concluded: June 27, 2018
Published: July 01, 2018
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Mahendhar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 3.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.