eMedicine Specialties > Endocrinology > Thyroid

Euthyroid Hyperthyroxinemia

Author: Reetu Singh, MD, Fellow, Department of Internal Medicine, Beebe Medical Center
Coauthor(s): Serge A Jabbour, MD, Associate Professor, Department of Medicine, Division of Endocrinology, Thomas Jefferson University
Contributor Information and Disclosures

Updated: Jul 23, 2008

Introduction

Background

Euthyroid hyperthyroxinemia is defined as a condition in which the serum total or, rarely, the free thyroxine (T4) concentrations are abnormal without evidence of clinical thyroid disease. These changes may be transient or persistent and may be associated with normal, low, or high triiodothyronine (T3) levels.¹

Pathophysiology

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.

T4 and T3 circulate in the blood bound to 3 different binding proteins, ie, thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA, or transthyretin (TTR), and albumin.

Approximately 99.97% of circulating T4 and 99.7% of circulating T3 are bound to these proteins. TBG carries 70% of the circulating T4 and T3 due to its high affinity. TBPA binds to only approximately 10-15% of the hormones (mostly T4), and albumin binds to the remaining 10-15%.

In comparison, T3 is less avidly bound to TBG and TBPA.

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) has a prevalence rate of 0.08-0.17% in white persons.

International

FDH is the most common cause of inherited elevation of serum T4 in white persons. Rare occurrences of FDH also have been reported in a Japanese family and in China.^2,3

Mortality/Morbidity

• Most of the conditions resulting in euthyroid hyperthyroxinemia do not have any adverse clinical outcomes.
• An exception to this is the syndrome of thyroid hormone resistance; children with this disorder may have learning difficulties because of hypothyroidism. The mortality associated with this condition is unknown.

Race

• No race predilection exists in nonhereditary euthyroid hyperthyroxinemia.
• FDH is observed most frequently in Hispanic and Portuguese people. Rare cases of FDH in Japanese and Chinese persons have been reported^2,3 ; no cases of FDH have been reported in black persons.

Sex

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

Age

• Most of the causes may be observed in any age group. However, thyroid hormone resistance may present in infancy or early childhood.

Clinical

History

Patients with euthyroid hyperthyroxinemia usually are asymptomatic. However, some patients affected with thyroid hormone resistance may present with the symptoms of hypothyroidism or hyperthyroidism, as follows:

• Symptoms of hypothyroidism may include the following:
  • Growth retardation
  • Delayed bone maturation
  • Learning disabilities
  • Mental retardation
  • Sensorineural deafness
• Symptoms of hyperthyroidism may include the following:
  • Typical symptoms - Absent
  • Children with thyroid hormone resistance - May had attention deficit hyperactivity disorder.⁴

A history of drug intake may include the following⁵ :

• Oral contraceptives or estrogen replacement⁶
• Amiodarone
• Propranolol⁷
• Heparin
• Perphenazine
• Clofibrate
• 5-fluorouracil

A history of drug abuse may include the following:

• Heroin
• Methadone treatment

The patient's menstrual history may include the following:

• Amenorrhea (pregnancy)
• Delayed puberty (thyroid hormone resistance)

A history of chronic diseases may include the following:

• Liver diseases - Active hepatitis, chronic hepatitis, biliary cirrhosis
• Human immunodeficiency virus (HIV) infection⁸
• Acute intermittent porphyria
• Malignant diseases - Islet cell tumors and glucagonomas

A history of psychiatric conditions may include acute psychosis.

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. Thyroid hormone resistance signs include the following:

• Goiter
• Nystagmus
• Tachycardia
• Increased metabolic rate
• Deafness

Liver disease signs include the following:

• Icterus
• Hepatomegaly

Causes

• Physiologic conditions
  • The most common physiologic condition resulting in elevated TBG concentrations is a normal pregnancy.
  • Estrogens stimulate the production of TBG by the liver and increase the glycosylation of TBG, which reduces its clearance. As a result, the total T4 and T3 are elevated, but T3 resin uptake is decreased, resulting in normal free T4 and T3 levels.
  • In newborns, the increased TBG most likely is due to the transplacental transfer of estrogens.⁹
• Hereditary causes - Several inherited abnormalities of thyroid hormone–binding proteins are now recognized, as follows^10,11,12 :
  • Increased TBG
    • Hereditary TBG excess is an X-linked disorder that results in increased synthesis of TBG, with normal immunoreactivity and binding affinity for thyroid hormones.¹³
    • 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 TBPA¹⁴
    • Euthyroid hyperthyroxinemia due to hereditary TBPA excess has also been described.
    • 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.
  • FDH¹⁵
    • FDH is a genetic disorder that occurs primarily in Hispanic people.
    • This condition is characterized by the presence of a mutant form of albumin, which is produced by an Arg-His substitution at codon 218.¹⁶ This form of albumin has an increased affinity 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 thyroid-stimulating hormone (TSH) level, total T3 level, and free T3 index are normal.
    • This mutation is seen in white persons; however, in the Japanese family in which this condition was found, the mutation at codon 218 resulted in an Arg-Pro substitution.³
    • 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, because this is an autosomal dominant condition.
    • 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, the albumin had a markedly increased affinity for T3 only. The condition was called familial dysalbuminemic hypertriiodothyroninemia.
• Drugs causing hyperthyroxinemia⁵
  • Estrogenic preparations increase the production of TBG 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.¹⁹ 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 T3.⁷
• Thyroid hormone resistance syndrome¹⁵
  • In compensated generalized thyroid hormone resistance, the total and the free T4 and T3 levels are elevated, with normal or slightly elevated TSH levels in the absence of any signs of hyperthyroidism. The inheritance usually is autosomal dominant, but it can be recessive in 10% of the cases.
  • Most patients are euthyroid, but some may have goiter, stunted growth, delayed menstruation, hyperactivity disorders, and resting tachycardia.⁴
  • The defect has been postulated to lie in the postreceptor processes, in the nonnuclear T3 receptors, or in qualitative abnormalities of nuclear T3 receptors.
• Hyperthyroxinemia of systemic illness
  • In most patients with systemic illness, the total and free serum T3 levels are reduced because of decreased peripheral deiodination of T4 into T3 (due to the inhibition of 5'-deiodinase). This results in a modest increase in the serum total T4 concentration, which may occur in 2% of patients who are acutely ill and in some patients with hyperemesis gravidarum.
  • 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 also result in increased TBG levels due 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
  • 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.
  • Anti-T3 immunoglobulins can lead to a falsely high total T3 level.
  • Through a mechanism that is not yet clear, extremely high altitudes can cause similar biochemical abnormalities in thyroid function.

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