What is the role of T3 (triiodothyronine) in a patient with autoimmune thyroid disease, such as Hashimoto's thyroiditis, and hypothyroidism?

The Role of T3 (Triiodothyronine) in Autoimmune Thyroid Disease

T3 (triiodothyronine) is the metabolically active thyroid hormone that directly regulates cellular metabolism, and in Hashimoto's thyroiditis with hypothyroidism, the thyroid gland preferentially produces T3 over T4 as a compensatory mechanism to maintain euthyroidism despite declining thyroid function. 1

T3's Physiological Function

T3 is the primary active thyroid hormone at the cellular level, responsible for:

• Regulating basal metabolic rate and energy expenditure in all tissues 1
• Controlling cardiovascular function, including heart rate, cardiac output, and myocardial contractility 1
• Maintaining normal thermogenesis and body temperature regulation 1
• Supporting cognitive function and mental state, with deficiency causing fatigue and mood disturbances 2

T3 Production in Hashimoto's Thyroiditis

In patients with Hashimoto's thyroiditis and subclinical hypothyroidism, the thyroid gland demonstrates "T3 euthyroidism"—a state where T3 levels remain normal or even elevated while T4 levels decline. 3

Compensatory Mechanisms

• The T3/T4 ratio increases significantly (2.46 ± 1.04% in Hashimoto's patients vs. 1.80 ± 0.64% in other hypothyroid states), indicating preferential T3 production 3
• TSH elevation correlates strongly with increased T3/T4 ratio (r=0.77), demonstrating that rising TSH drives the thyroid to produce more T3 relative to T4 3
• This compensatory mechanism maintains normal metabolism despite declining overall thyroid function, explaining why patients may remain clinically euthyroid with elevated TSH 3

Metabolic Basis

• Iodine metabolism disturbances in Hashimoto's thyroid favor T3 production over T4 synthesis 3
• When basal T3 levels are already elevated, the thyroid shows no further T3 response to TRH stimulation, indicating the gland is functioning at maximum capacity with no reserve remaining 3

Clinical Implications for Treatment

Standard Levothyroxine (T4) Monotherapy

Levothyroxine (T4) alone is the standard first-line treatment for hypothyroidism, including Hashimoto's thyroiditis, as it allows physiologic peripheral conversion to T3. 1

• T4 monotherapy provides stable, consistent thyroid hormone levels without the wide serum T3 swings seen with direct T3 administration 4
• Target TSH should be 0.5-4.5 mIU/L with normal free T4 levels to ensure adequate T3 production through peripheral conversion 1

When T3 Supplementation May Be Considered

Some patients with Hashimoto's thyroiditis may benefit from combined T4/T3 therapy, particularly those with persistent symptoms despite normalized TSH on T4 monotherapy. 2

• Substituting 10 mcg of T3 for 50 mcg of T4 can improve psychological functioning and mental state in select patients 2
• Combined therapy may improve mood scales and symptoms of hypothyroidism in women with autoimmune thyroiditis 2
• Patients with DIO2 gene polymorphisms may have impaired T4-to-T3 conversion and benefit more from combination therapy 1

Dosing Considerations for T3

If T3 supplementation is used, start with 5 mcg daily and increase by 5-10 mcg every 1-2 weeks, with usual maintenance doses of 25-75 mcg daily for mild hypothyroidism. 4

• T3 has rapid onset and dissipation of action, with metabolic effects persisting only a few days after discontinuation 4
• Wide swings in serum T3 levels following administration increase the risk of cardiovascular side effects compared to T4 monotherapy 4
• Once-daily dosing is recommended despite the short half-life 4

Special Considerations in Hashimoto's Thyroiditis

Thyroid Hormone Autoantibodies

Patients with Hashimoto's thyroiditis may develop autoantibodies against T3 and/or T4, causing falsely abnormal laboratory values and potential hormone resistance. 5, 6

• Anti-T3 antibodies occur more commonly than anti-T4 antibodies in Hashimoto's patients 6
• These antibodies can cause falsely low or undetectable T3/T4 measurements by standard radioimmunoassay 6, 7
• Ethanol extraction of sera reveals true T3 levels, which may be normal or elevated despite low measured values 6
• Severe hormone-resistant hypothyroidism may require treatment with liothyronine (T3) when T4 autoantibodies prevent effective T4 therapy 7

Monitoring During Treatment

Monitor TSH and free T4 every 6-8 weeks during dose titration, then every 6-12 months once stable. 1

• Free T3 measurement is not routinely necessary for monitoring standard hypothyroidism treatment 1
• If T3 autoantibodies are suspected (paradoxically high free T4 with high TSH and low T3 resin uptake), measure T3 by equilibrium dialysis 7
• Declining autoantibody titers may allow transition from T3 to T4 therapy in patients initially requiring liothyronine 7

Critical Pitfalls to Avoid

• Never assume normal T3 levels exclude hypothyroidism—TSH is the primary screening test, and "T3 euthyroidism" can mask declining thyroid function 3
• Avoid initiating T3 therapy without first optimizing T4 dosing, as most patients achieve adequate T3 levels through peripheral conversion 1
• Do not overlook thyroid hormone autoantibodies in patients with paradoxical laboratory findings (high TSH with high free T4 or discordant T3/T4 values) 6, 7
• Recognize that approximately 25% of patients on levothyroxine are unintentionally overtreated with suppressed TSH, increasing cardiovascular and bone risks 1