Euthyroid Hyperthyroxinemia 

Updated: Feb 01, 2018
Author: Justyna Kotus, MD; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

Euthyroid hyperthyroxinemia is defined as a condition in which the serum total thyroxine (T4) and triiodothyronine (T3) concentrations are increased, but the thyroid-stimulating hormone (TSH) concentration is normal and there are no clinical signs or symptoms of thyroid dysfunction. These changes may be transient or persistent.[1]

In the past, euthyroid hyperthyroxinemia was a diagnostic challenge and many patients were inappropriately treated for thyroid disease. Today, serum TSH is a screening test for thyroid function, and a normal TSH value should not be followed by measurement of total T4. In these circumstances, euthyroid hyperthyroxinemia frequently remains undetected with no harm to the patients.

Related Medscape topics include Hypothyroidism, Pediatric Hypothyroidism, Neurological Manifestations of Thyroid Disease, and Thyroid Dysfunction Induced by Amiodarone Therapy.

Pathophysiology

Both thyroxine (T4) and triiodothyronine (T3) circulate in the blood bound to the following three different binding proteins:

  • Thyroxine-binding globulin (TBG)

  • Thyroxine-binding prealbumin (TBPA), or transthyretin (TTR)

  • Albumin

Approximately 99.97% of circulating T4 and 99.7% of circulating T3 are bound to these proteins. TBG carries 75% of the circulating T4 and T3, owing to its high affinity. TBPA binds to only approximately 15% of the hormones (mostly T4), and albumin binds to the remaining 10%. In comparison, T3 is less avidly bound to TBG and TBPA.

Serum total T4 and T3 assays measure both bound and free (unbound) hormone. As a result, factors that alter binding protein concentrations have profound effects on serum total T4 and T3 concentrations even though serum free T4 and T3 do not change and the patient is euthyroid.

The various causes of hyperthyroxinemia in patients who are euthyroid are listed in Causes. Among them, the most common cause is an increase in the levels of serum binding proteins

Epidemiology

Frequency

United States

Because this condition is characterized by a number of different disorders, its true prevalence is unknown. However, among the hereditary conditions, familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of inherited elevation of serum T4 in white populations and its prevalence rate is 0.08-0.17%. Rare occurrences of FDH have also been reported in a Japanese and Chinese families.[2, 3]

Mortality/Morbidity

Most of the conditions resulting in euthyroid hyperthyroxinemia do not have any adverse clinical outcomes.

Race

No race predilection exists in nonhereditary euthyroid hyperthyroxinemia. Familial dysalbuminemic hyperthyroxinemia (FDH) is a genetic disorder, most often occurring in patients of Latino and Portuguese background. Rare cases of FDH in Japanese and Chinese families have been reported[2, 3] ; no cases of FDH have been reported in the African American population.

Sex

No sex predilection exists for any of the conditions (except those associated with pregnancy).

Age

Most of the causes may be observed in any age group. Older men who are frail may manifest higher free thyroxine levels.[4, 5]

 

Presentation

History

Patients with euthyroid hyperthyroxinemia are usually asymptomatic.

A history of drug intake may include the following[6] :

  • Oral contraceptives or estrogen replacement[7]

  • Amiodarone

  • Propranolol[8]

  • Heparin

  • Perphenazine[9]

  • Clofibrate[9]

  • 5-Fluorouracil[10]

  • Lithium[11]

A history of drug abuse may include the following:

  • Heroin[12]

  • Methadone[12]

A history of chronic diseases may include the following:

  • Liver diseases - Active hepatitis, chronic hepatitis, biliary cirrhosis

  • Human immunodeficiency virus (HIV) infection[13]

  • Acute intermittent porphyria

  • Malignant diseases - Islet cell tumors and glucagonomas

A history of psychiatric conditions, including acute psychosis, can be associated.

The patient's family history is an important aspect of diagnosis because one of the most revealing clues in the diagnosis of hereditary conditions is the discovery of another family member with the same laboratory abnormalities.

Physical

Patients with euthyroid hyperthyroxinemia do not manifest any physical signs other than those pertinent to their underlying pathology.

Causes

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.[14]

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.[15]

Hereditary causes

Several inherited abnormalities of thyroid hormone–binding proteins are now recognized.[16, 17, 18]

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,[19] 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)[20]

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.[21] Euthyroid hyperthyroxinemia has been described in association with substitution of alanine in codon 109 with valine or threonine.[21, 22]

Familial dysalbuminemic hyperthyroxinemia (FDH)[23]

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.[24] 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[25] and Swiss origin.[26, 27]

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.[28]

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.[29, 30]

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.

Drugs causing hyperthyroxinemia[6]

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.[31] 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.[8]

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.[32] 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.[33]

Extremely high altitudes can cause similar biochemical abnormalities in thyroid function (mechanism is unclear).

 

DDx

 

Workup

Laboratory Studies

In resolving the cause of an elevated thyroxine (T4) level, consider the following:

  • Obtain a detailed clinical evaluation (ie, history, associated medical conditions, drugs, family history) and pay particular attention to the absence or presence of signs that are suggestive of hyperthyroidism.

  • Measure thyroid-stimulating hormone (TSH) by a third-generation assay showing the lack of suppression, except in hyperemesis gravidarum and severe systemic illness.

  • Measure free T4, especially by equilibrium dialysis (criterion standard). Free T4 is normal except in certain instances, such as when drugs (eg, heparin, propranolol, amiodarone, contrast agents) are being used or when acute psychosis, systemic illness, or hyperemesis gravidarum is present.[8, 34]

Imaging Studies

No imaging studies are required to diagnose this condition.

 

Treatment

Medical Care

Persons with the familial form of euthyroid hyperthyroxinemia do not require any medical care. Avoidance of the causative drugs may be helpful.

Activity

No restriction of activity is necessary.

 

Medication

Medication Summary

By definition, persons with euthyroid hyperthyroxinemia do not have any clinical thyroid disease; therefore, treatment is not indicated.

 

Follow-up

Further Outpatient Care

Ensure careful follow-up of patients with chronic diseases.

Further Inpatient Care

No further inpatient care is indicated.

Inpatient & Outpatient Medications

No medications are indicated.

Complications

No adverse clinical outcomes from the hereditary disorders exist. Complications in the other conditions are related to the primary disorder.

Prognosis

The prognosis depends on the underlying pathophysiology; however, most of the conditions are self-limiting, except the familial and neoplastic disorders.

Patient Education

Inform patients with the familial form of the disorder that this condition is harmless and does not require any treatment.