Why order anti‑thyroid peroxidase (anti‑TPO) antibodies in a 60‑year‑old woman with overt hyperthyroidism (suppressed TSH, elevated free T4) and possible autoimmune adrenal insufficiency?

Why Order Anti-TPO Antibodies in Hyperthyroidism?

Anti-TPO antibodies should be ordered in hyperthyroidism because they identify autoimmune etiology and help distinguish between Graves' disease and other causes of thyrotoxicosis, while also predicting risk of progression to hypothyroidism and screening for associated autoimmune conditions like adrenal insufficiency.

Anti-TPO Antibodies Are Present in Both Hyperthyroid and Hypothyroid Autoimmune Disease

The key misconception is that anti-TPO antibodies are specific to hypothyroidism—they are not. Anti-TPO antibodies are present in 74% of Graves' disease patients (hyperthyroid) and 99.3% of Hashimoto's thyroiditis patients (hypothyroid), making them a marker of thyroid autoimmunity rather than thyroid function status 1.

• Anti-TPO antibodies identify an autoimmune etiology for thyroid dysfunction, even when thyroid function tests show hyperthyroidism 1.
• The presence of anti-TPO antibodies in hyperthyroidism confirms that the underlying process is autoimmune (Graves' disease) rather than toxic nodular goiter, thyroiditis, or exogenous thyroid hormone 2, 3.
• In patients with overt hyperthyroidism, 53-64% will have elevated anti-TPO antibodies if the cause is Graves' disease 2, 4.

Distinguishing Graves' Disease from Destructive Thyroiditis

In a patient with suppressed TSH and elevated free T4, anti-TPO antibodies help differentiate between:

• Graves' disease (persistent hyperthyroidism requiring antithyroid drugs, radioiodine, or surgery)
• Hashimoto's thyroiditis in thyrotoxic phase (transient hyperthyroidism that will progress to hypothyroidism)
• Painless thyroiditis (self-limited, requires only symptomatic management)

During acute inflammatory flares in Hashimoto's, TSH may temporarily decrease due to thyroid cell destruction releasing stored hormone, which can be mistaken for hyperthyroidism but typically transitions to hypothyroidism 1. This is critical because the management is entirely different—destructive thyroiditis requires watchful waiting, not antithyroid drugs 1.

Predicting Progression to Hypothyroidism

Even in the hyperthyroid phase, anti-TPO antibodies predict future thyroid failure:

• Patients with positive anti-TPO antibodies have a 4.3% per year risk of developing overt hypothyroidism versus 2.6% per year in antibody-negative individuals 1.
• Treatment of autoimmune hyperthyroidism (Graves' disease) resulted in a median decrease in anti-TPO levels of over 50% after reaching the euthyroid state, whereas in persistent hyperthyroidism no consistent changes were observed 2.
• Regular monitoring of thyroid function (TSH, free T4) every 6-12 months is essential in anti-TPO positive patients, regardless of whether they have Graves' disease or are at risk for Hashimoto's thyroiditis 1.

Screening for Associated Autoimmune Conditions

The presence of anti-TPO antibodies is associated with other autoimmune conditions, suggesting potential benefit in screening for conditions like type 1 diabetes, celiac disease, or adrenal insufficiency 1. This is particularly relevant in your 60-year-old woman with possible autoimmune adrenal insufficiency.

• Screening for Addison's disease/adrenal insufficiency with 21-hydroxylase antibodies (21OH-Ab) or adrenocortical antibodies is recommended when anti-TPO antibodies are present 1.
• The European Society of Human Reproduction and Embryology specifically advises screening for 21-hydroxylase antibodies in patients with positive anti-TPO antibodies to detect concurrent adrenal autoimmunity 1.
• Patients with autoimmune thyroiditis have increased risk of multiple autoimmune conditions, including type 1 diabetes, celiac disease, pernicious anemia, and primary adrenal insufficiency 1.

Diagnostic Accuracy and Clinical Utility

• With a cut-off point of 200 units/ml, anti-TPO testing achieves 96% sensitivity for Hashimoto's thyroiditis and 59% sensitivity for Graves' disease with 100% specificity 2.
• Clearly elevated anti-TPO values (>500 units/ml) were found in 59% of patients with thyroiditis but in none of the controls or patients with non-thyroidal illness 2.
• The highest frequency of positive results (88-90%) was obtained in patients with autoimmune hypothyroidism, followed by patients with Graves' disease (53-64%) 2, 4.

Common Pitfalls to Avoid

• Do not assume anti-TPO antibodies are only relevant in hypothyroidism—they are a marker of thyroid autoimmunity that appears in both hyper- and hypothyroid autoimmune disease 1, 3.
• Recognize that the absence of anti-TPO antibodies does not exclude Graves' disease—approximately 26-47% of Graves' patients will be anti-TPO negative 2, 4.
• Avoid missing the transient thyrotoxic phase of Hashimoto's thyroiditis, which presents with hyperthyroidism but will progress to hypothyroidism; anti-TPO antibodies help identify these patients 1.
• Always consider screening for adrenal insufficiency in patients with positive anti-TPO antibodies, especially when clinical features suggest polyglandular autoimmune syndrome 1.

Practical Algorithm for Your Patient

In a 60-year-old woman with overt hyperthyroidism (suppressed TSH, elevated free T4) and possible autoimmune adrenal insufficiency:

1. Order anti-TPO antibodies to confirm autoimmune etiology 1, 3
2. Order TRAb (TSH receptor antibodies) to distinguish Graves' disease from thyroiditis 1
3. Screen for 21-hydroxylase antibodies given the concern for adrenal insufficiency 1
4. If anti-TPO positive with low/normal TRAb: suspect Hashimoto's thyroiditis in thyrotoxic phase—manage conservatively and monitor for progression to hypothyroidism 1
5. If both anti-TPO and TRAb positive: diagnose Graves' disease—initiate antithyroid drugs, beta-blockers, and plan definitive therapy 1
6. Screen for other autoimmune conditions: celiac disease, type 1 diabetes, pernicious anemia 1

The presence of anti-TPO antibodies in hyperthyroidism is not a contradiction—it is essential diagnostic information that guides management, predicts disease course, and identifies patients requiring screening for associated autoimmune conditions 1, 3, 5.