Euthyroid Hyperthyroxinemia

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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:

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]

History

Patients with euthyroid hyperthyroxinemia are usually asymptomatic.

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

A history of drug abuse may include the following:

A history of chronic diseases may include the following:

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).

Laboratory Studies

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

Imaging Studies

No imaging studies are required to diagnose this condition.

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 Summary

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

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.

Author

Justyna Kotus, MD, Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Jane V Mayrin, MD, FACE, Staff Attending Physician, Einstein Endocrine Associates, Albert Einstein Medical Center; Staff Endocrinologist, Kindred Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Romesh Khardori, MD, PhD, FACP, Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor Emeritus of Medicine, St Louis University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Steven R Gambert, MD, Professor of Medicine, Johns Hopkins University School of Medicine; Director of Geriatric Medicine, University of Maryland Medical Center and R Adams Cowley Shock Trauma Center

Disclosure: Nothing to disclose.

Acknowledgements

Serge A Jabbour, MD, FACP, FACE Professor of Medicine, Division of Endocrinology, Diabetes and Metabolic Diseases, Jefferson Medical College of Thomas Jefferson University

Serge A Jabbour, MD, FACP, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Medical Association, American Thyroid Association, Pennsylvania Medical Society, and The Endocrine Society

Disclosure: Nothing to disclose.

Reetu Singh, MD Fellow, Department of Internal Medicine, Beebe Medical Center

Reetu Singh, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Thyroid Association, and The Endocrine Society

Disclosure: Nothing to disclose.

References

  1. Borst GC, Eil C, Burman KD. Euthyroid hyperthyroxinemia. Ann Intern Med. 1983 Mar. 98(3):366-78. [View Abstract]
  2. 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. 1999 Oct. 141(4):374-8. [View Abstract]
  3. 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. 1997 Oct. 82(10):3246-50. [View Abstract]
  4. Yeap BB, Alfonso H, Chubb SA, Walsh JP, Hankey GJ, Almeida OP, et al. Higher free thyroxine levels are associated with frailty in older men. The Health In Men Study. Clin Endocrinol (Oxf). 2011 Nov 11. [View Abstract]
  5. Yeap BB, Alfonso H, Hankey G, Flicker L, Golledge J, Norman PE, et al. Higher free thyroxine levels are associated with all-cause mortality in euthyroid older men. The Health In Men Study. Eur J Endocrinol. 2013 Jul 12. [View Abstract]
  6. 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. [View Abstract]
  7. Sänger N, Stahlberg S, Manthey T, et al. Effects of an oral contraceptive containing 30 mcg ethinyl estradiol and 2 mg dienogest on thyroid hormones and androgen parameters: conventional vs. extended-cycle use. Contraception. 2008 Jun. 77(6):420-5. [View Abstract]
  8. Mooradian A, Morley JE, Simon G, et al. Propranolol-induced hyperthyroxinemia. Arch Intern Med. 1983 Nov. 143(11):2193-5. [View Abstract]
  9. McKerron CG, Scott RL, Asper SP, Levy RI. Effects of clofibrate (Atromid S) on the thyroxine-binding capacity of thyroxine-binding globulin and free thyroxine. J Clin Endocrinol Metab. 1969 Jul. 29(7):957-61. [View Abstract]
  10. Beex LV, Ross A, Smals AG, Kloppenborg PW. Letter: 5-fluorouracil and the thyroid. Lancet. 1976 Apr 17. 1(7964):866-7. [View Abstract]
  11. Chekuri L, Lange JR, Thapa PB. Lithium-induced transient euthyroid hyperthyroxinemia: a case report. Prim Care Companion CNS Disord. 2014. 16(2):[View Abstract]
  12. Azizi F, Vagenakis AG, Portnay GI, Braverman LE, Ingbar SH. Thyroxine transport and metabolism in methadone and heroin addicts. Ann Intern Med. 1974 Feb. 80(2):194-9. [View Abstract]
  13. Wiener M, Lo Y, Klein R. Abnormal thyroid function in older men with or at risk for HIV infection. HIV Med. 2008 Jun 11. [View Abstract]
  14. Vaidya B, Hubalewska-Dydejczyk A, Laurberg P, Negro R, Vermiglio F, Poppe KG. Treatment and Screening of Hypothyroidism in Pregnancy: Results of a European Survey. Eur J Endocrinol. 2011 Oct 24. [View Abstract]
  15. Kvetny J, Poulsen H. Transient hyperthyroxinemia in newborns from women with autoimmune thyroid disease and raised levels of thyroid peroxidase antibodies. J Matern Fetal Neonatal Med. 2006 Dec. 19(12):817-22. [View Abstract]
  16. Moses AC, Rosen HN, Moller DE, et al. A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia. J Clin Invest. 1990 Dec. 86(6):2025-33. [View Abstract]
  17. Hishinuma A, Mochizuki Y, Kasai K, et al. [Thyroxine-binding proteins--familial euthyroid hyperthyroxinemia due to point mutations of transthyretin]. Nippon Rinsho. 1994 Apr. 52(4):886-9. [View Abstract]
  18. Magalhães PK, Rodrigues Dare GL, Rodrigues Dos Santos S, et al. Clinical features and genetic analysis of four Brazilian kindreds with resistance to thyroid hormone. Clin Endocrinol (Oxf). 2007 Nov. 67(5):748-53. [View Abstract]
  19. Tucker WS Jr. Euthyroid hyperthyroxinemia due to familial excess of thyroxine-binding globulin. South Med J. 1989 Mar. 82(3):368-71. [View Abstract]
  20. 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). 1989 Jan. 120(1):87-91. [View Abstract]
  21. Refetoff S, Marinov VS, Tunca H, Byrne MM, Sunthornthepvarakul T, Weiss RE. A new family with hyperthyroxinemia caused by transthyretin Val109 misdiagnosed as thyrotoxicosis and resistance to thyroid hormone--a clinical research center study. J Clin Endocrinol Metab. 1996 Sep. 81(9):3335-40. [View Abstract]
  22. Moses AC, Rosen HN, Moller DE, Tsuzaki S, Haddow JE, Lawlor J, et al. A point mutation in transthyretin increases affinity for thyroxine and produces euthyroid hyperthyroxinemia. J Clin Invest. 1990 Dec. 86(6):2025-33. [View Abstract]
  23. Gharib H, Klee GG. Familial euthyroid hyperthyroxinemia secondary to pituitary and peripheral resistance to thyroid hormones. Mayo Clin Proc. 1985 Jan. 60(1):9-15. [View Abstract]
  24. Rushbrook JI, Becker E, Schussler GC, et al. Identification of a human serum albumin species associated with familial dysalbuminemic hyperthyroxinemia. J Clin Endocrinol Metab. 1995 Feb. 80(2):461-7. [View Abstract]
  25. Schoenmakers N, Moran C, Campi I, et al. A novel albumin gene mutation (R222I) in familial dysalbuminemic hyperthyroxinemia. J Clin Endocrinol Metab. 2014 Jul. 99(7):E1381-6. [View Abstract]
  26. Wada N, Chiba H, Shimizu C, Kijima H, Kubo M, Koike T. 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. 1997 Oct. 82(10):3246-50. [View Abstract]
  27. Pannain S, Feldman M, Eiholzer U, Weiss RE, Scherberg NH, Refetoff S. Familial dysalbuminemic hyperthyroxinemia in a Swiss family caused by a mutant albumin (R218P) shows an apparent discrepancy between serum concentration and affinity for thyroxine. J Clin Endocrinol Metab. 2000 Aug. 85(8):2786-92. [View Abstract]
  28. Greenberg SM, Ferrara AM, Nicholas ES, Dumitrescu AM, Cody V, Weiss RE, et al. A novel mutation in the Albumin gene (R218S) causing familial dysalbuminemic hyperthyroxinemia in a family of Bangladeshi extraction. Thyroid. 2014 Jun. 24(6):945-50. [View Abstract]
  29. 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. [View Abstract]
  30. George PM, Sheat JM, Palmer BN. Detection of protein binding abnormalities in euthyroid hyperthyroxinemia. Clin Chem. 1988 Sep. 34(9):1745-8. [View Abstract]
  31. Jackson JA, Verdonk CA, Spiekerman AM. Euthyroid hyperthyroxinemia and inappropriate secretion of thyrotropin. Recognition and diagnosis. Arch Intern Med. 1987 Jul. 147(7):1311-3. [View Abstract]
  32. Loh TP, Leong SM, Loke KY, Deepak DS. Spuriously elevated free thyroxine associated with autoantibodies, a result of laboratory methodology: case report and literature review. Endocr Pract. 2014 Aug 1. 20(8):e134-9. [View Abstract]
  33. Cogan E, Abramow M. Transient hyperthyroxinemia in symptomatic hyponatremic patients. Arch Intern Med. 1986 Mar. 146(3):545-7. [View Abstract]
  34. Stockigt JR, Barlow JW. The diagnostic challenge of euthyroid hyperthyroxinemia. Aust N Z J Med. 1985 Apr. 15(2):277-84. [View Abstract]