Thyroxine-Binding Globulin Deficiency


Article Author:
Varshini Chakravarthy


Article Editor:
Sehar Ejaz


Editors In Chief:
Linda Lindsay


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James Hughes
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Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
6/14/2019 9:14:09 PM

Introduction

Thyroxine-binding globulin (TBG) is one of three major transport proteins, which are primarily responsible for binding to and transporting thyroid hormones to the necessary tissues.  The other two serum transport proteins include transthyretin and human serum albumin.  While there are higher amounts of albumin in serum, TBG has a greater affinity to thyroxine (T4).[1] Abnormalities in the functionality and amount of TBG can cause variations in the total amount of T4 in the serum, but not in the amount of bioactive free T4.  Since the amount of free T4 circulating in the serum remains the same, deficiency in thyroxine-binding globulin often does not lead to adverse metabolic effects seen in an individual with abnormal thyroid hormone levels.[2] However, it can cause errors in the interpretation of thyroid hormone labs, which can ultimately lead to inappropriate treatment.  This article illustrates the etiology, diagnosis, and management of thyroxine-binding globulin deficiency. 

Etiology

Thyroxine-binding globulin (TBG) is a serine protease inhibitor produced in the liver. It belongs to the SERPINA7 family. The encoding gene for this protein is on the long arm of the X chromosome and as such, inherited forms of TBG tend to follow an X-linked pattern. Approximately 27 different mutations have been identified to play a role in the etiology of the inherited form of complete TBG deficiency thus far. These mutations seem to be caused by a nucleotide substation or by a frameshift.  Missense mutations have been the only type identified so far in an inherited form of partial TBG deficiency.[1]

Acquired forms of TBG deficiency are attributable to degradation and altered synthesis of the molecule. Patients with hyperthyroidism have been found to have an increase in the rate of turnover of TBG.  In terminal illness, interleukin-6 seems to play a role in altering the levels of TBG. Levels of TBG have been found to vary with fluctuations in sex hormones as well.  For example, estrogen has been known to cause an increase in TBG, while androgens have been found to decrease levels TBG.[3]

Epidemiology

The most common inherited form of TBG deficiency is partial TBG deficiency with a prevalence of 1 in 4000 newborns.  Complete TBG deficiency has an incidence of 1 per 15000 male newborns. There has been no reported increase in the predilection of TBG deficiency in a particular race.[4]

Pathophysiology

The primary function of TBG is to help maintain the constant pool of thyroid hormone in the serum.  Research estimates that in the absence of new thyroid hormone production, the amount already present in the serum would be used within just a few hours.  However, in the presence of TBG, there would be only a 10% drop in T4 and a 40% drop in T3. As such, TBG can also be noted to play a role in preventing thyroid hormone fluctuations.[3]

When there is a decrease in TBG, the levels of free T4 increase and negatively inhibit TSH, resulting in a reduction of the total T4 produced. Thus, the total T4 decreases and the free T4 in serum returns to normal levels.[5]

History and Physical

Though there are no clinical signs and symptoms particular to TBG deficiency, there is usually a strong family history in inherited forms of TBG deficiency.  Patients with acquired TBG deficiency may present with symptoms consistent with an underlying illness such as severe liver disease or protein-wasting nephropathy.  The patient's history could also suggest the use of anabolic steroids or androgens. Physical examinations are within normal limits, in both acquired and inherited forms and any variation are usually be attributable to a secondary disease process.[6] For example, a female patient with complete TBG deficiency may present with features of Turner syndrome, including webbed neck and short stature.[7]

Evaluation

In cases of inherited thyroid binding globulin deficiency, the disorder is often picked up on the newborn screening during the evaluation of congenital hypothyroidism. The newborn screening often looks at either TSH, total T4, or both.   If the total T4 is below the serum cut off, the screen comes back as a positive result.[8] Confirmatory testing with TBG, free T4, and TSH help rule out congenital hypothyroidism and rule in the diagnosis of TBG deficiency.[9] Thyroxine-binding globulin has been found to be present in the serum of a fetus as early as at 12 weeks gestation. The level of TBG is approximately 1.5 times that of an adult until adolescence at which point it starts to decrease.[10] Affected boys have been found to have mild, moderate and severe changes in thyroid hormone levels; whereas girls have been rarely found to have critical changes in thyroid hormone levels except in the instance of Turner syndrome. The normal level TBG in an adult male is 1.1 to 2.1 mg/dl.[3] In a hemizygous male with complete TBG deficiency, TBG is found to be below 5 mg/L. In hemizygous females with partial TBG deficiency, serum levels of TBG are near normal.[1]  TBG deficiency can also present as an incidental finding.  In such cases, if other causes of TBG deficiency are ruled out, suspicion for inherited TBG deficiency should be high and should prompt genetic testing for confirmation.  

Treatment / Management

Management of secondary illness, causing acquired TBG deficiency, may improve levels of TBG.  However, replacement with l-thyroxine is not required, as there is no change in the levels of metabolically active free T4 levels. 

Differential Diagnosis

The differential diagnosis for TBG deficiency includes central hypothyroidism and euthyroid sick syndrome. Laboratory testing for patients with central hypothyroidism shows low FT4, low Total T4 along with low or inappropriately normal TSH levels. Central hypothyroidism may be congenital or acquired. Some critically ill euthyroid patients with non-thyroidal illness may also present with low FT4, low T4 along with low TSH. However, most of these patients present with high reverse T3 levels due to reduced clearance of Reverse T3. These abnormalities usually resolve with resolution of non-thyroid illness. 

Prognosis

TBG deficiency is a benign condition, and the prognosis is favorable. Patients with inherited forms need reassurance only and should receive education about the nature of the condition. 

Complications

Complications can arise from misinterpretation of total T4 levels. As such, iatrogenic symptoms and the manifestations of hyperthyroidism may occur as a result of inappropriate treatment with levothyroxine.

Deterrence and Patient Education

Evidence-based resources for patients with TBG deficiency include the following:

  1. Inherited Thyroxine Binding Deficiency – U.S. National Library of Medicine Website
  2. Thyroxine-Binding Globulin Deficiency – Medscape
  3. Serum Thyroxine-Binding Globulin (TBG) Level Test- Healthline

Enhancing Healthcare Team Outcomes

TBG deficiency is a benign disease state subject to easy misdiagnosis as hypothyroidism.  It is important for the clinician to assess the patient appropriately for symptoms of thyroid disease. Though most patients with TBG deficiency are clinically euthyroid, there have been case reports that illustrate concomitant disease with other thyroid abnormalities such as Graves disease.  As such, clinicians should possess a low threshold to refer to endocrinology when patients have a known history of other thyroid disease states and are now presenting with TBG deficiency even if they are euthyroid.[11]  It may also provide patient benefit to refer the patient to genetics workup if there is a strong family history of this disorder. 

In summary, TBG deficiency requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


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Thyroxine-Binding Globulin Deficiency - Questions

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An 11-year-old obese male comes to the clinic for a routine visit. His BMI and weight are above the 97th percentile, and his height is in the 85th percentile. He has a heart rate of 88 beats per minute, and blood pressure is 120/81 mmHg. He has no temperature intolerance, no constipation, or diarrhea and denies dry skin. Thyroid function test show TSH 2.3 mIU/L (0.3-4.2 mIU/l), total T4 3.5 microg/dL (5.5-12.8 microg/dL) and free T4 1.1 /ng/dL (0.76-1.46 ng/dL), Which of the following best idenfities the gene implicated in this disorder?



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A 2-day old baby boy is brought to the office by his parents after he is found to have failed the newborn screen for a normal TSH and a low T4. Which of the following lab results would suggest a diagnosis of thyroxine-binding globulin deficiency?



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A 10-year-old obese male has been referred to the clinic for elevated BMI. His BMI and weight are above the 97th percentile, and his height is in the 80th percentile. He has a heart rate of 85 beats per minute, and blood pressure is 116/80 mmHg. He has no temperature intolerance, fatigue, no constipation or diarrhea and denies dry skin. As part of initial obesity work up, thyroids function tests are ordered. Thyroid-stimulating hormone (TSH) is 1.4 mIU/L (0.3-4.2 mIU/l) and total T4 is 3.5 mcg/dL (5.5-12.8 mcg/dL). Which of the following best describes the most common mode of inheritance of his disorder?



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A 2-day-old baby girl is being evaluated for a failed newborn screen showing normal TSH and low T4. A normal free T4 confirms the diagnosis. In which of the following disorders can the complete manifestation of this disease be seen in, given the patient's gender?



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An 8-year-old male with type 1 diabetes presents to the clinic for follow up. As part of routine lab work, he is found to have normal TSH, low total T4, and a normal free T4. His BMI, weight, and height are in the 25th percentile, and he is following the curve appropriately. He has a heart rate of 85 beats per minute, and blood pressure is 116/80 mmHg. He has no temperature intolerance, no constipation or diarrhea and denies dry skin. Which of the following is the next best step in the management of this patient?



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A 4-year-old female presents to the clinic for short stature. Her physical exam is significant for webbed neck, high arched palate, and a low hairline. She had also been referred to cardiology once for a murmur found on physical exam. Her vitals are within normal limits, and she has no symptoms. Thyroid function tests are performed, but no need for any treatment is found based on the results. Which of the following lab results are consistent with the diagnosis?



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A 9-year-old male has thyroid workup done due to elevated BMI. He is asymptomatic, and his vitals are within normal limits. Thyroid-stimulating hormone is 1.6 mIU/L (0.3-4.2 mIU/l), total T4 is 2.5 mcg/dL (5.5-12.8 mcg/dL), and free T4 is 1.3 /ng/dL (0.76-1.46 ng/dL).Which one of the following diseases share a similar inheritance pattern as the most common form of this patient’s disorder?



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Thyroxine-Binding Globulin Deficiency - References

References

Pappa T,Ferrara AM,Refetoff S, Inherited defects of thyroxine-binding proteins. Best practice     [PubMed]
Ferrara AM,Pappa T,Fu J,Brown CD,Peterson A,Moeller LC,Wyne K,White KP,Pluzhnikov A,Trubetskoy V,Nobrega M,Weiss RE,Dumitrescu AM,Refetoff S, A novel mechanism of inherited TBG deficiency: mutation in a liver-specific enhancer. The Journal of clinical endocrinology and metabolism. 2015 Jan;     [PubMed]
Refetoff S, Thyroid Hormone Serum Transport Proteins 2000;     [PubMed]
Refetoff S, Inherited thyroxine-binding globulin abnormalities in man. Endocrine reviews. 1989 Aug;     [PubMed]
Franklyn J,Shephard M, Evaluation of Thyroid Function in Health and Disease 2000;     [PubMed]
Berger HR,Creech MK,Hannoush Z,Watanabe Y,Kargi A,Weiss RE, A NOVEL MUTATION CAUSING COMPLETE THYROID BINDING GLOBULIN DEFICIENCY (TBG-CD MIA) IN A MALE WITH COEXISTING GRAVES DISEASE. AACE clinical case reports. 2017 Spring;     [PubMed]
Refetoff S, Abnormal Thyroid Hormone Transport 2000;     [PubMed]
Neto EC,Rubin R, Thyroxine-binding globulin in neonates and children. The Western journal of medicine. 2001 Nov;     [PubMed]
Rastogi MV,LaFranchi SH, Congenital hypothyroidism. Orphanet journal of rare diseases. 2010 Jun 10;     [PubMed]
Jin HY, Thyroxine binding globulin excess detected by neonatal screening. Annals of pediatric endocrinology     [PubMed]
Dall'Aglio E,Robuschi G,Minelli R,Guerra M,Bentivoglio M,Roti E, Graves' disease and thyroxine-binding globulin deficiency. Archives of internal medicine. 1988 Jun;     [PubMed]

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