Thyroxine binding globulin (TBG)

Overview

Thyroxine-binding globulin (TBG) is one of the three major serum transport proteins responsible for binding and carrying thyroid hormones to tissues. Produced in the liver, TBG is a glycoprotein and a member of the SERPINA7 family of serine protease inhibitors.

It binds about 75% of circulating thyroxine (T4) and triiodothyronine (T3), maintaining a reservoir of thyroid hormones in the bloodstream and regulating the fraction of free hormone available to tissues. Compared to other transport proteins like transthyretin and albumin, TBG has a lower binding capacity but a much higher affinity, especially for T4.

Normal reference intervals for TBG vary by age, gender, and physiological state. For example, adult males typically show 1.2–2.5 mg/dL, while adult females show 1.4–3.0 mg/dL. During pregnancy or with oral contraceptive use, levels may rise significantly.

Symptoms

Altered TBG levels do not directly cause disease but influence thyroid function test results, which may mimic symptoms of thyroid imbalance. Because TBG affects total T4/T3 but not free T4/T3, patients may appear to have hyperthyroidism or hypothyroidism if TBG changes are not considered.

1. High TBG (↑ total T4/T3, normal free T4/T3):
   1. Symptoms may resemble hyperthyroidism, such as palpitations, anxiety, heat intolerance, and weight loss.
2. Low TBG (↓ total T4/T3, normal free T4/T3):
   1. Symptoms may resemble hypothyroidism, such as fatigue, weight gain, cold intolerance, and sluggishness.

These symptoms arise not from TBG itself but from misinterpretation of thyroid function tests if TBG levels are not accounted for.

Causes

Several physiological conditions, diseases, and medications can alter TBG concentrations:

1. Causes of Increased TBG:
   1. Estrogen exposure (oral contraceptives, estrogen therapy)
   2. Pregnancy (especially third trimester, ~5.3 ± 0.6 mg/dL)
   3. Certain medications such as phenothiazines, valproic acid, and opioids
   4. Acute intermittent porphyria
2. Causes of Decreased TBG:
   1. Hypothyroidism
   2. Liver disease (since TBG is produced in the liver)
   3. High doses of salicylates (e.g., aspirin)
   4. Medications such as phenytoin, carbamazepine, and glucocorticoids (e.g., prednisone)
   5. Male hormones (androgens and testosterone)

Thus, both hormonal and non-hormonal influences can disrupt TBG levels and complicate thyroid disorder evaluation.

Risk Factors

Certain populations are more prone to altered TBG levels:

1. Pregnant Women: Due to elevated estrogen, TBG rises significantly.
2. Oral Contraceptive Users: Estrogen-containing OCPs increase TBG levels.
3. Patients with Liver Disease: Reduced hepatic synthesis lowers TBG production.
4. Individuals with Hypothyroidism: Thyroid dysfunction may reduce TBG levels.
5. Medication Users:
   1. Drugs like valproic acid, carbamazepine, phenytoin, and glucocorticoids lower TBG.
   2. Estrogen therapy, opioids, and phenothiazines elevate TBG.

Recognizing these risk factors is crucial to avoid misdiagnosis of thyroid disorders.

Prevention

Direct prevention of altered TBG levels is often not possible since many causes are physiological (like pregnancy) or therapeutic (medication use). However, preventive strategies focus on accurate interpretation of thyroid tests and minimizing avoidable influences:

1. Awareness in Testing:
   1. Always measure free T4 and T3, not just total hormone levels, to avoid errors caused by TBG fluctuations.
   2. Use reference ranges adjusted for age, sex, and physiological states like pregnancy.
2. Medication Management:
   1. Inform clinicians about current medications that may interfere with TBG levels.
   2. Avoid unnecessary high doses of drugs known to alter TBG.
3. Liver Health Maintenance:
   1. Since TBG is produced in the liver, preventing or managing liver diseases can help maintain stable TBG levels.
4. Patient Education:
   1. Pregnant women and individuals on estrogen therapy should be counseled that high TBG levels may affect thyroid test interpretation.
   2. Patients should understand that TBG changes do not necessarily reflect thyroid disease.