AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

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.

Both T4 and T3 circulate in the blood bound to 3 different binding proteins, ie, thyroxine-binding globulin (TBG), transthyretin (TTR) or thyroxine-binding prealbumin (TBPA), 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. TTR binds to only approximately 10-15% of the hormones (mostly T4), while albumin binds to the remaining 10-15%.

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

Frequency

United States

Because this condition is characterized by a number of different disorders, 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.

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 racial predilection exists in nonhereditary conditions.
• FDH is observed most frequently in Hispanic and Portuguese people. Although relatives of a Japanese and Chinese family with FDH have been reported, 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

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

• 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 be hyperactive
     
• History of drug intake may include the following:
• • Oral contraceptives or estrogen replacement
  
  
  
  • Amiodarone
  
  
  
  • Propranolol
  
  
  
  • Heparin
  
  
  
  • Perphenazine
  
  
  
  • Clofibrate
  
  
  
  • 5-Fluorouracil
     
• History of drug abuse may include the following:
• • Heroin
  
  
  
  • Methadone treatment
     
• Menstrual history may include the following:
• • Amenorrhea (pregnancy)
  
  
  
  • Delayed puberty (thyroid hormone resistance)
     
• History of chronic diseases may include the following:
• • Liver diseases - Active hepatitis, chronic hepatitis, biliary cirrhosis
  
  
  
  • HIV infection
  
  
  
  • Acute intermittent porphyria
  
  
  
  • Malignant diseases - Islet cell tumors and glucagonomas
     
• History of psychiatric conditions may include acute psychosis.



• Family history is an important aspect of diagnosis because one of the most important clues in diagnosing hereditary conditions is discovering 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

Many conditions can result in elevated levels of thyroid hormones with no clinical evidence of hyperthyroidism. These may be grouped as follows:

• Physiologic conditions
• • The most common physiologic condition resulting in an elevation of 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.
     
• Hereditary causes: Several inherited abnormalities of thyroid hormone–binding proteins are now recognized, as follows:
• • Increased thyroxin-binding globulin
    
    
    • Hereditary TBG excess is an X-linked disorder that results in increased synthesis of TBG, with normal immunoreactivity and binding affinity for thyroid hormones.
    
    
    
    • 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 thyroxin-binding prealbumin
    
    
    • Euthyroid hyperthyroxinemia also has been described due to hereditary TBPA excess.
    
    
    
    • Because TBPA mostly carries T4 and not T3, the T3 resin uptake does not help detect this condition, resulting in a falsely elevated free T4 index, but free T4 levels measured by radioimmunoassay or equilibrium dialysis are normal.
       
  • Familial dysalbuminemic hyperthyroxinemia
    
    
    • FDH is a genetic disorder that mostly occurs in Hispanic people.
    
    
    
    • This condition is characterized by the presence of a mutant form of albumin due to an Arg-His substitution at position 218 of the codon. This form of albumin has an increased affinity for T4 but not T3. The increased binding of T4 results in normal T3 resin uptake but an elevated free T4 index. In these patients, 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 observed to have this condition, the mutation at codon 218 resulted in an Arg-Pro substitution.
    
    
    
    • 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 the 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 by radioimmunoassay. The abnormal albumin level can be demonstrated by thyroid hormone–binding protein electrophoresis.
    
    
    
    • Another variant of albumin described in a Thai family, in which the albumin had a marked increased affinity for T3 only, was called familial dysalbuminemic hypertriiodothyroninemia.
       
• Drugs causing hyperthyroxinemia
• • Estrogenic preparations increase the production and reduce the clearance of TBG (see Physiologic conditions, above). 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 all block the conversion of T4 into T3, causing an elevation in T4 and reverse T3 with a decreased T3 level. In addition, these drugs may cause an elevation of TSH, which also is due to their inhibition of conversion of T4 to T3 in the central nervous system, thereby interfering with the feedback regulation of pituitary thyrotropin secretion. However, the effect is transient (few months) because of the escape phenomenon.
  
  
  
  • Heparin, even when administered subcutaneously, may cause an increase in the serum free T4 levels. This occurs because of stimulation of lipoprotein lipase by heparin, which generates free fatty acids, which then inhibit the binding of T4 to TBG.
  
  
  
  • Propranolol also inhibits extrathyroidal conversion of T4 into T3.
     
• Thyroid hormone resistance syndrome
• • 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 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.
  
  
  
  • The defect has been postulated to lie in the postreceptor processes, nonnuclear T3 receptors, or 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 to T3 due to 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) result in high levels of TBG from increased production and reduced clearance due to 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, central activation of the hypothalamic-pituitary axis has been postulated to possibly contribute 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 and resulting 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 also can lead to a falsely high total T3 level.
  
  
  
  • Extremely high altitudes can cause similar biochemical abnormalities in thyroid function through an unclear mechanism.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• In resolving the cause of an elevated 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 suggestive of hyperthyroidism.

  • Measure 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), which is normal except in some conditions such as drug use (eg, heparin, propranolol, amiodarone, contrast agents), acute psychosis, systemic illness, and hyperemesis gravidarum.

Imaging Studies

• No imaging studies are required to diagnose this condition.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

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

Surgical Care

The tumors, such as glucagonoma, islet cell tumors, or estrogen-secreting tumors, may be resectable, which may lead to resolution of the abnormality postoperatively.

Activity

No restriction of activity is necessary.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• No further inpatient care is indicated.

Further Outpatient Care

• Ensure careful follow-up of patients with chronic diseases.

In/Out Patient Meds

• No medications are indicated.

Complications

• No adverse clinical outcomes from the hereditary disorders exist, but the 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 the neoplastic disorders.

Patient Education

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

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Most of the conditions may be mistaken for hyperthyroidism, and treatment may be initiated based on thyroid function tests. Evaluating the patient thoroughly is important, with respect to the clinical examination and the necessary tests, to avoid potentially harmful and unnecessary treatment.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Borst GC, Eil C, Burman KD. Euthyroid hyperthyroxinemia. Ann Intern Med. Mar 1983;DA - 19830407(3):366-78. [Medline].
• Eber O, Langsteger W, Florian W, et al. [Evaluating thyroid gland function in patients with protein anomalies]. Acta Med Austriaca. 1991;18(1):11-9. [Medline].
• George PM, Sheat JM, Palmer BN. Detection of protein binding abnormalities in euthyroid hyperthyroxinemia. Clin Chem. Sep 1988;34(9):1745-8. [Medline].
• Gharib H, Klee GG. Familial euthyroid hyperthyroxinemia secondary to pituitary and peripheral resistance to thyroid hormones. Mayo Clin Proc. Jan 1985;60(1):9-15. [Medline].
• Hishinuma A, Mochizuki Y, Kasai K, Shimoda S. [Thyroxine-binding proteins--familial euthyroid hyperthyroxinemia due to point mutations of transthyretin]. Nippon Rinsho. Apr 1994;52(4):886-9. [Medline].
• Jackson JA, Verdonk CA, Spiekerman AM. Euthyroid hyperthyroxinemia and inappropriate secretion of thyrotropin. Recognition and diagnosis. Arch Intern Med. Jul 1987;147(7):1311-3. [Medline].
• Maye P, Bisetti A, Burger A, et al. Hyperprealbuminemia, euthyroid hyperthyroxinemia, Zollinger-Ellison-like syndrome and hypercorticism in a pancreatic endocrine tumour. Acta Endocrinol (Copenh). Jan 1989;120(1):87-91. [Medline].
• Molashenko NV, Sviridenko NIu, Platonova NM, et al. [The specific features of thyrotoxicosis and euthyroid hyperthyroxinemia developed due to the use of cordarone]. Klin Med (Mosk). 2004;82(12):35-9. [Medline].
• Mooradian A, Morley JE, Simon G, Shafer RB. Propranolol-induced hyperthyroxinemia. Arch Intern Med. Nov 1983;143(11):2193-5. [Medline].
• Moses AC, Rosen HN, Moller DE, et al. A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia. J Clin Invest. Dec 1990;86(6):2025-33. [Medline].
• Rushbrook JI, Becker E, Schussler GC, Divino CM. Identification of a human serum albumin species associated with familial dysalbuminemic hyperthyroxinemia. J Clin Endocrinol Metab. Feb 1995;80(2):461-7. [Medline].
• Stockigt JR, Barlow JW. The diagnostic challenge of euthyroid hyperthyroxinemia. Aust N Z J Med. Apr 1985;15(2):277-84. [Medline].
• Tang KT, Yang HJ, Choo KB, et al. A point mutation in the albumin gene in a Chinese patient with familial dysalbuminemic hyperthyroxinemia. Eur J Endocrinol. Oct 1999;141(4):374-8. [Medline].
• Tucker WS Jr. Euthyroid hyperthyroxinemia due to familial excess of thyroxine-binding globulin. South Med J. Mar 1989;82(3):368-71. [Medline].
• Wada N, Chiba H, Shimizu C, et al. A novel missense mutation in codon 218 of the albumin gene in a distinct phenotype of familial dysalbuminemic hyperthyroxinemia in a Japanese kindred. J Clin Endocrinol Metab. Oct 1997;82(10):3246-50. [Medline].

Article Last Updated: Jan 13, 2006