Hypothyroidism and hyperthyroidism are common and often the result of thyroid autoimmunity. The widespread availability of thyroid serum antibody laboratory tests may raise questions from patients and clinicians.
What do thyroid antibodies really tell us? Here is an overview of the most ordered serum thyroid antibodies as interpreted in common clinical scenarios.
Case #1: Thyroid antibodies in Hashimoto’s thyroiditis
A healthy 24-year-old woman has elevated titers of thyroid anti-thyroidase antibodies (TPOAb) and anti-thyroglobulin antibodies (TgAb) within the normal thyroid-stimulating hormone (TSH) range of 3.5 mIU/mL and free thyroxine (T4) of 0.9 ng/dL. She is asymptomatic. Her mother has type 1 diabetes and Hashimoto’s thyroiditis. She asks, “What do my positive thyroid antibodies mean?”
Referrals for patients like this are common for endocrinologists. Serum TPOAb and TgAb positivity is associated with Hashimoto’s thyroiditis (HT), also known as chronic lymphocytic thyroiditis. These antibodies can affect thyroid hormone synthesis and cause thyroid dysfunction (usually hypothyroidism). While the TPOAb could directly attack the thyroid glandTPOAb levels may also reflect a chronic immune response involving both T and B cell-mediated immunity (Khoury and his colleagues; Ramos-Levi and Marazuela). About 90% of patients with HT will have positive TPOAb titerswhile only 50% will have a positive TgAb level.
We informed our patient that she had an increased risk of developing thyroid dysfunction over time, on the order of 1% to 2% per year (Tunbridge and his colleagues; Vanderpump and his colleagues; Huber and his colleagues) due to chronic thyroid inflammation and immune cell infiltration. We advised her to have her serum TSH and free T4 measured at least once a year and informed her of the symptoms of hypothyroidism. Although not relevant to her now, we also discussed that high levels of TPOAb and TgAb increase her risk of developing thyroid dysfunction during pregnancy or if she was placed on amiodarone for arrhythmias, lithium for psychiatric disorders, and tyrosine kinase inhibitors (ITK) or immune checkpoint inhibitors (HERE) for cancer.
Case #2: Thyroid antibodies in thyroid cancer surveillance
A 37-year-old man with a history of papillary thyroid cancer and a total thyroidectomy is seen for thyroid cancer surveillance. He is active in his care and wants to know more about how his cancer will be monitored over time.
With open access to patient data in electronic medical records, we have noticed that more and more patients want to know more about their thyroid cancer and what to expect regarding its monitoring. As endocrinologists, we are fortunate to have serum thyroglobulin (Tg) as a reliable tumor marker in differentiated thyroid cancer. Tg levels can be monitored after total thyroidectomy, whether or not radioactive iodine ablation is given, but are usually not useful in people who have had only hemithyroidectomy (Park and colleagues; Ritter and his colleagues). Increased Tg levels suggest persistent or recurrent thyroid cancer that may require further imaging or treatment. When TgAb levels are also present, however, Tg levels may not be reliable. It is important to always control TgAb and Tg levels, even if the TgAb is initially negative, as some patients may generate TgAb over time.
Most laboratories use an immunometric assay (IMA) to measure serum Tg levels in TgAb negative patients. IMA is automated, inexpensive, has fast turnaround times and good accuracy. However, approximately 10% to 20% of patients will have positive TgAb levels which may interfere with the IMA test; in such cases, artificially low Tg levels may be observed, leading to erroneous assurance. In patients with positive AcTg levels by AMI, measure them by radioimmunoassay is preferred. Newer tests such as mass spectroscopy have also shown promise in patients with positive TgAb levels, but may still yield false-negative Tg values (Netzel and his colleagues; Spencer and his colleagues).
Case #3: Thyroid antibodies in Graves’ disease
A healthy 52-year-old woman recently had persistent palpitations. Serum TSH is < 0.02 mIU/mL (reference, 0.3-4.7 mIU/mL), free T4 is 5.70 ng/dL (reference, 0.8-1.7 ng/dL) and free triiodothyronine (T3) is 1920 pg/dL (reference, 222-383 pg/nL). She has fine bilateral hand tremors and sinus tachycardia. How to elaborate this new diagnosis of thyrotoxicosis?
This is one of the most common queries we receive. Thyroid antibodies may be helpful in unraveling the differential diagnosis of thyrotoxicosis.
Anti-TSH receptor antibodies (TRAb) target the TSH receptor and can have an inhibitory, neutral or stimulatory effect. The thyrotropin binding inhibitor immunoglobulin (TBII) test measures antibodies that inhibit the binding of TSH to its receptor. Stimulating TRAbs, known as thyroid-stimulating immunoglobulins (TSI), are associated with Graves’ disease; they stimulate the TSH receptor, leading to increased production and release of thyroid hormones. Although names may vary in commercial labs, positive TBII, TRAb, or TSI titers can all be used to diagnose Graves’ disease. These antibodies are cost effective, have quick turnaround times, and are more convenient than radioiodine uptake assays. Since TRAbs also bind to orbital fibroblasts and muscle cells, they can cause proptosis and ocular muscle hypertrophy, called thyroid eye disease. Thyroid antibody levels can monitor the risk and response to treatment of thyroid eye disease, which does not always reflect the biochemical severity of hyperthyroidism.
Our patient was started on a short course of propranolol to manage hyperthyroidism. A few days later, his TSI titer result was 10 times higher than the upper limit of normal, confirming Graves’ disease. After starting methimazole, we can track his serum TSI levels to predict chances of future remission.
Case #4: Thyroid antibodies in the use of TKI and ICI
We received a message from the oncologist of a patient who had put the patient on pembrolizumab, an anti-protein programmed cell death (PD-1) ICI, for metastatic melanoma. Thyroid screening labs performed with his fourth round of treatment showed TSH < 0.02 mIU/mL and free T4 of 3.40 ng/dL, suggesting ICI-induced thyroiditis.
With the emergence of TKIs and ICIs in anti-cancer treatments, there is an increase in associated thyroiditis. ICI thyroiditis occurs in 10% to 25% of patients, who are usually asymptomatic and have decreased radioactive iodine uptake consistent with destructive thyroiditis (Iyer and his colleagues; Muir and his colleagues; Peiró and his colleagues). Serum TgAb and TPOAb are often absent and not necessary for diagnosis (Iyer and his colleagues; de Moel and colleagues; Mazarico and his colleagues).
ICI thyroiditis is destructive; it is not motivated by TSIs, and although TRAb is sometimes detected, these laboratory results are taken into account secondary to robust immune response rather than contributing to the underlying pathogenesis.
TKI-associated hypothyroidism occurs in up to 40% of patients and is associated with the progressive development of permanent hypothyroidism (Lechner and his colleagues; Torino and his colleagues). Thyroid antibodies are often absent. Interestingly, thyroid dysfunctions associated with TKIs and ICIs have been associated with a better response to cancer treatment; they are not a reason to stop or interrupt cancer treatment (Peiró and his colleagues; de Moel and colleagues; Mom and her colleagues).
Case #5: Thyroid antibodies during pregnancy
A 31-year-old woman with a history of miscarriage and Hashimoto’s thyroiditis (Ac TPO positive) has just confirmed a 7-week pregnancy. How should this patient be monitored or treated?
Thyroid hormone is necessary for the normal development of the fetus (Leung and his colleagues; Smallridge and his colleagues). The risks of adverse pregnancy outcomes, including miscarriage, are increased in women with positive TPOAb levels and higher TSH concentrations. The American Thyroid Association recommended start levothyroxine in TPOAb-positive women with TSH > 2.5 mIU/mL and consider levothyroxine in TPOAb-negative women with TSH levels between the upper limit of the reference range and 10 mIU/mL. After starting levothyroxine, thyroid labs should be checked every 1-2 months during pregnancy.
It is also important to remember that in pregnant women with current or previous Graves’ disease, serum TRAb measurements can provide useful prognostic information about the fetus, as antibodies stimulating TSH receptors can cross the placenta. for increase the risk of fetal hyperthyroidism. Serum TSI Headlines May Still Be Positive pose this risk, even if the mother is no longer hyperthyroid or has an intact thyroid gland.
Thyroid autoantibodies are an important tool in the diagnosis and management of thyroid disease (including Hashimoto’s thyroiditis and Graves’ disease), in monitoring thyroid cancer, and in optimizing hormone status thyroid during pregnancy. As these tests are readily available in most laboratories, we hope this summary will be helpful in their interpretation and in the management of these common thyroid conditions.