A complete thyroid test usually includes two parts: indicators reflecting the functional status of the thyroid gland (including T3, T4, FT3, FT4, TSH, etc.), and thyroid autoantibodies related to the cause (such as TRAb, TgAb, TPOAb, etc.). People are often familiar with the former; however, the clinical significance of the latter is generally not well understood. In clinical practice, people often ask: What do the different antibodies mean? What does an increased or decreased antibody level mean? Is the goal of clinical treatment to correct the nail function abnormality or to get the antibodies to turn negative? Here we will discuss the issues involved.
1. Overview of thyroid autoantibodies
Thyroid autoantibodies are immunoglobulins produced by autoimmune disorders that target certain components of the thyroid gland. There are two main clinical categories.
(1) Antibodies directed against TSH receptors on the surface of thyroid cells, i.e., TSH receptor antibodies.
(2) Antibodies against thyroid cell contents, including thyroid peroxidase antibodies and thyroglobulin antibodies.
2. Typing of TRAb, clinical significance and indications for testing
TSH receptor antibodies are a heterogeneous group of specific immunoglobulins, divided into two subtypes: thyroid-stimulating antibodies, which are associated with the development of autoimmune hyperthyroidism (i.e. Graves’ disease), and thyroid-blocking antibodies, which are associated with autoimmune hypothyroidism (mainly Hashimoto’s disease).
It should be noted that the currently clinically detected TRAb only reflects the presence of autoantibodies against the TSH receptor and does not reflect the function of such antibodies. When the clinical presentation is consistent with GD disease, TRAb is generally considered as TSH receptor stimulating antibody (i.e., TSAb). When the clinical presentation is consistent with hypothyroidism or Hashimoto’s disease, the TRAb is generally regarded as a TSH receptor blocking antibody (i.e. TBAb).
Clinical significance.
(1) TRAb (here, stimulating antibody, i.e., TSAb) can be an important basis for the diagnosis of Graves’ disease (toxic diffuse goiter) and for the identification of various clinical causes of hyperthyroidism. the rate of positive TRAb in patients with Graves’ disease can be over 95%, while other causes of hyperthyroidism are generally negative.
(2) TRAb (here refers to stimulating antibody, i.e. TSAb) can be used to determine the efficacy of antithyroid drugs and the prognosis of Graves’ disease; a negative TRAb indicates that the body is in immune remission, and the patient’s thyroid function is normalized by antithyroid drugs, and the disease is not likely to recur after stopping the drugs; a positive TRAb indicates that the body is in an active immune state, and there is a higher possibility of recurrence after stopping the drugs. It has been reported in the literature that those who are still positive for TRAb after one year of antithyroid drug (ATD) treatment have a relapse rate of 90% within three years.
(3) Predicting neonatal hyperthyroidism: Because TRAb can cross the placenta for transport, a TRAb-positive pregnant woman can cause transient hyperthyroidism in the newborn (incidence 1 to 2%).
(4) It helps to diagnose Graves’ ophthalmopathy with normal nail function. Some patients with proptosis have normal thyroid function, but if TR-Ab is strongly positive, the diagnosis of Graves’ ophthalmopathy can also be confirmed.
(5) Identification of the cause of hypothyroidism: If a hypothyroid patient has a positive TRAb, the hypothyroidism is caused by thyroid stimulating blocking antibody (TBAb).
Indications.
(1) For differential diagnosis of hyperthyroidism (is it autoimmune or other causes?) (2) Graves’ ophthalmopathy.
(2) Diagnosis and evaluation of Graves’ ophthalmopathy.
(3) Follow-up of pregnant women with Graves’ disease (including newborns).
(4) follow-up of Graves’ disease treatment (predicting the probability of recurrence and deciding when to stop the drug).
(5) Check for the presence of blocking antibodies (i.e. TBAb) for the evaluation of hypothyroidism.
3. Clinical significance of TPO-Ab and Tg-Ab and indications for testing
Thyroid peroxidase antibodies (TPO-Ab) and thyroglobulin antibodies (Tg-Ab) are caused by damage to thyroid cells and the spillage of intracytoplasmic “peroxidase” (a key enzyme for thyroid hormone synthesis) and “thyroglobulin” into the bloodstream. TPO-Ab has the same clinical significance as TG-Ab, but TPO-Ab has better sensitivity and specificity than TGAb and is the first choice for diagnosing autoimmune thyroid disease. In order to increase the positive detection rate, a combination of the two antibodies is usually used in clinical practice.
Clinical significance.
(1) Etiological diagnosis: These antibodies are the main basis for the diagnosis of autoimmune thyroid disease (AITD). Significant elevations (strong positivity) are mainly seen in chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), while moderate elevations are commonly seen in toxic diffuse goiter (i.e. Graves’ disease); in addition, they can also be used for the differential diagnosis of AITD and non-AITD, e.g., primary hypothyroidism In addition, it can also be used for the differential diagnosis of AITD and non-AITD, for example, the differentiation of primary hypothyroidism from secondary hypothyroidism, where the former is positive for TPO-Ab and Tg-Ab, and the latter is negative.
(2) Efficacy observation: TPO-Ab and Tg-Ab turn negative or titer decreases after treatment in patients with Graves’ disease, indicating good efficacy; if the antibody continues to be positive and titer is high, it means the effect is not good and the disease is prone to relapse after stopping the medication.
(3) Prognosis: Elevated TPO-Ab and Tg-Ab indicate an increased risk of hypothyroidism in the future. For example, persistent positive TPO-Ab and Tg-Ab in pregnant women indicates a higher risk of “postpartum thyroiditis” and “infantile hypothyroidism”.
(4) TgAb can also be used as a monitoring indicator for differentiated thyroid cancer (TDC): under normal circumstances, the TgAb level of patients with differentiated thyroid cancer will gradually decrease after radical surgery and turn negative within one to four years, if the TgAb level increases again, it often indicates tumor recurrence.
Indications
TPO-Ab and Tg-Ab tests are used to determine the cause of thyroid disease and to assess the risk of developing thyroid disorders in patients with
(1) Those with elevated TSH of unknown etiology.
(2) patients with goiter of unknown etiology
(3) Differential diagnosis of hyperthyroidism of unknown etiology.
(4) Suspected polyglandular autoimmune disease.
(5) Familial evaluation of autoimmune thyroid disorders.
(6) Evaluation of the risk of inducing thyroid disorders during treatment with thyroid-acting drugs (e.g., lithium salts, amiodarone) or drugs acting on the immune system (e.g., interferon).
(7) Risk assessment of postpartum thyroiditis (during pregnancy or postpartum).
4. Clinical evaluation of thyroid autoantibodies
(1) The specificity of thyroid antibodies is not strong and low to moderate levels of TPO-Ab and/or Tg-Ab can be detected in the sera of not only patients with autoimmune thyroid disease (AITD) but also some healthy individuals (26% in adult females and 9% in males), therefore, caution should be exercised when evaluating their clinical significance.
(2) Antibody levels often overlap between patients and healthy individuals and between different diseases (e.g., between Graves’ disease and Hashimoto’s thyroiditis); therefore, clinical diagnosis should not rely exclusively on antibody levels, but should be analyzed and judged in conjunction with the patient’s medical history, clinical manifestations, thyroid function, ultrasound, and cytology.
(3) There is no direct relationship between the level of thyroid antibodies (Tg-Ab, TPO-Ab, etc.) and the severity of thyroid function abnormalities. For example, in the late stage of Hashimoto’s disease, when the thyroid follicles are extensively atrophied and degenerated, antibody levels may not even be high.
(4) A positive TRAb supports the diagnosis of Graves’ disease, but a negative TRAb does not exclude Graves’ disease. For hyperthyroidism patients with negative TRAb, if the TPOAb is significantly elevated, Graves’ disease can also be diagnosed.
(5) The goal of treatment for thyroid disease is to correct thyroid abnormalities, not to turn antibodies negative (of course, it is better to turn antibodies negative). Considering the side effects of immunosuppressive therapy, the long-term use of glucocorticoids and immunosuppressive drugs is generally not recommended for the purpose of antibody reversion.
(6) Although it has been suggested that the level of TRAb before treatment is positively correlated with the course of treatment in patients with Graves’ disease, if the clinical and laboratory tests of hyperthyroidism have been normalized after treatment and the course of treatment has reached the requirements, the course of treatment should not be extended indefinitely because the TRAb has not turned negative.
(7) The greatest significance of antibody testing is to assist in clinical diagnosis and assessment of efficacy and prognosis.