Many conditions can be associated with a high serum thyroxine (T4) concentration, and, sometimes, with free T4 concentration with normal serum thyroid-stimulating hormone (TSH) level and no clinical evidence of hyperthyroidism. [1] This should always alert the physician to search for one of the causes of euthyroid hyperthyroxinemia. These conditions may be grouped as described below.
Physiologic conditions
Pregnancy is the most common physiologic condition resulting in elevated thyroxine-binding globulin (TBG) concentrations. [2]
Conditions with high estrogen levels are causes. Estrogen stimulates the production of TBG by the liver and increases the glycosylation of TBG, which reduces its clearance. As a result, the total T4 and triiodothyronine (T3) levels are elevated, but T3 resin uptake is decreased, resulting in normal free T4 and T3 levels.
In newborns, increased TBG is most likely due to estrogen transplacental transfer. [3]
Hereditary causes
Several inherited abnormalities of thyroid hormone–binding proteins are now recognized. [4, 5, 6]
Increased TBG
This is the most common binding protein abnormality. It is an X-linked dominant disorder.
Increased synthesis of TBG, with normal immunoreactivity and binding affinity for thyroid hormones, [7] occurs. Because TBG has a high affinity for T4 and T3, the total concentrations of both hormones are elevated.
The diagnosis can be made by direct measurement of TBG by radioimmunoassay.
Increased thyroxine-binding prealbumin (TBPA) [8]
Because TBPA carries T4 far more often than it does T3, the T3 resin uptake does not help in the detection of this condition. A falsely elevated free T4 index results from this condition; however, free T4 levels measured by radioimmunoassay or equilibrium dialysis are normal.
TTR mutation
Serum transthyretin transports about 20% of total T4. [9] Euthyroid hyperthyroxinemia has been described in association with substitution of alanine in codon 109 with valine or threonine. [9, 10]
Familial dysalbuminemic hyperthyroxinemia (FDH) [11]
FDH is the most common cause of increased total T4 levels, with a prevalence of about 1 case in 10,000 population. It most commonly in patients of Latino origin.
FDH is an autosomal dominant condition, and multiple different mutations have been identified.
Arginine to histidine substitution in codon 218 has been described. [12] This form of albumin has a low affinity and high capacity for T4 but not for T3. The increased binding of T4 results in normal T3 resin uptake, but an elevated free T4 index. In patients with FDH, the serum TSH, total T3 level, and free T3 index are normal. It is most commonly seen in whites, but can also occur in Chinese and Latino populations.
Arginine to proline substitution in codon 218 has been described in patients of Japanese [13] and Swiss origin. [14, 15]
Arginine to isoleucine substitution in codon 222 has been described in families of Croatian and Somalian origin.
Arginine to serine substitution has been described in a Bangladeshi family, with total T4 levels 9 times higher than normal despite being clinically euthyroid. [16]
The diagnosis can be established by performing a resin uptake with radiolabeled T4 instead of T3. Alternatively, the serum T4 and free T4 index can be measured in family members.
Free T4 levels are normal when measured by equilibrium dialysis; in contrast, the free T4 hormone may be falsely elevated in a radioimmunoassay. The abnormal albumin level can be demonstrated by thyroid hormone–binding protein electrophoresis. [17, 18]
In another albumin variant described in a Thai family (L66P mutation), the albumin had 40-fold increased affinity for T3 but only 1.5-fold for T4. The condition was called familial dysalbuminemic hypertriiodothyroninemia.
A study by Zhao et al described twoALBmutations, R218S and R218H, in eight Chinese families with FDH. [19]
Moran et al reported the cases of a young man and his grandmother with euthyroid hyperthyroxinemia due to anALBmutation (R218P) known to cause FDH. They also had hypercortisolemia; however, their serum-free cortisol levels were normal and total cortisol levels decreased markedly after depletion of albumin from their serum. [20]
Drugs causing hyperthyroxinemia [21]
Estrogenic preparations increase TBG production and reduce its clearance (see the above list of physiologic conditions). Heroin, methadone, clofibrate, perphenazine, and 5-fluorouracil also raise the levels of serum TBG by increasing its secretion by the liver.
Amiodarone, iopanoic acid, and ipodate block the conversion of T4 into T3, causing an elevation of T4; they also reverse T3, resulting in a decreased T3 level. In addition, these drugs may cause an elevation of TSH, which also is due to their inhibition of the conversion of T4 into T3 in the central nervous system, thereby interfering with the feedback regulation of pituitary thyrotropin secretion. [22] Because of the escape phenomenon, however, the effect is transient (lasting a few months).
Heparin, even when administered subcutaneously, may cause an increase in serum free T4 levels. This results from the stimulation of lipoprotein lipase by heparin, which generates free fatty acids. These fatty acids inhibit the binding of T4 to TBG.
Propranolol also inhibits extrathyroidal conversion of T4 into T3. [23]
Hyperthyroxinemia of systemic illness
Liver diseases (eg, acute infectious hepatitis, chronic active hepatitis, primary biliary cirrhosis) produce high levels of TBG from increased production and reduced clearance, the result of functional hyperestrogenemia. Estrogen-secreting tumors, acute intermittent porphyria, and HIV infection also result in increased TBG levels, owing to enhanced liver production.
Acute psychosis causes a modest elevation of total and free serum T4 concentrations in 1-10% of patients. Although the actual mechanism is unknown, it has been postulated that central activation of the hypothalamic-pituitary axis contributes to the abnormality. The elevation usually is transient and resolves in several weeks
Increased TBPA also has been reported in patients with glucagonoma and islet cell carcinomas.
Miscellaneous
Antithyroid hormone antibodies are autoantibodies targeted against T2, T3, and T4 that can cause spurious free T4 measurements. [24] The prevalence of these antibodies can be very high; however, they are associated with euthyroid hyperthyroxinemia in a small minority of patients. The development of autoantibodies has been described with specific medications, after fine-needle aspiration, or idiopathically. A few cases have been described in patients having monoclonal proteins targeted against the thyroid hormones in the setting of multiple myeloma or Waldenstrom macroglobulinemia.
The presence of anti-T4 immunoglobulins can cause a spuriously elevated level of total T4 when T4 is measured by radioimmunoassay. These immunoglobulins also bind radiolabeled T4, thereby preventing it from binding to the anti-T4 antibodies used in the assay; this results in a high serum total T4 value. Because these antibodies do not bind to T3, the thyroid hormone–binding ratio, as estimated by the T3 uptake, is normal. They can be detected by adding radiolabeled T4 to the patient's serum and precipitating the immunoglobulin fraction with polyethylene glycol.
Symptomatic hyponatremia may be associated with small increases in serum total T4 concentrations. [25]
Extremely high altitudes can cause similar biochemical abnormalities in thyroid function (mechanism is unclear).
