What is the treatment for a patient with a low Thyroid-Stimulating Hormone (TSH) level and normal free Thyroxine (T4) level?

Management of Low TSH with Normal Free T4

This presentation most likely represents subclinical hyperthyroidism requiring further evaluation to determine the underlying cause before initiating treatment. The key is distinguishing between primary thyroid disease, medication-induced suppression, immune checkpoint inhibitor effects, or central hypothyroidism—each requiring completely different management approaches.

Initial Diagnostic Algorithm

Repeat thyroid function tests (TSH and free T4) in 6-8 weeks before making definitive treatment decisions, as transient TSH suppression is common and may resolve spontaneously, particularly in the context of nonthyroidal illness or recent iodine exposure 1. However, for patients with atrial fibrillation, cardiac disease, or serious medical conditions, consider repeating thyroid function tests within 2 weeks rather than waiting the full interval 1.

Critical First Question: Is the Patient Taking Levothyroxine?

If the patient is taking levothyroxine, this represents iatrogenic subclinical hyperthyroidism and requires immediate dose reduction 1:

• Decrease levothyroxine by 25-50 mcg for TSH <0.1 mIU/L 1
• Decrease levothyroxine by 12.5-25 mcg for TSH 0.1-0.4 mIU/L 1
• Approximately 25% of patients on levothyroxine are inadvertently maintained on excessive doses, leading to significant morbidity including atrial fibrillation, osteoporosis, and cardiac complications 1

Second Critical Question: Is the Patient on Immune Checkpoint Inhibitors?

In patients receiving anti-CTLA4, anti-PD-1, or anti-PD-L1 therapy, low TSH with normal T4 often represents the hyperthyroid phase of destructive thyroiditis that typically precedes hypothyroidism 1:

• Monitor thyroid function tests every cycle for anti-CTLA4 therapy and every cycle for the first 3 months with anti-PD-1/PD-L1 1
• A falling TSH across two measurements with normal or lowered T4 may suggest pituitary dysfunction (hypophysitis)—immediately check 9 AM cortisol weekly 1
• If symptomatic hyperthyroidism develops, use beta-blockers (propranolol or atenolol) for symptom control 1
• Withhold checkpoint inhibitors only if the patient is unwell with symptomatic hyperthyroidism 1

Third Critical Question: Could This Be Central Hypothyroidism?

Low TSH with low or low-normal T4 strongly suggests pituitary or hypothalamic dysfunction, not hyperthyroidism 1. This pattern is particularly common with anti-CTLA4 therapy (incidence 1-16% depending on dose, 8% with combination therapy) 1.

Clinical suspicion of hypophysitis is frequently raised when routine thyroid function testing shows a low TSH with low free T4, suggestive of a central etiology 2:

• Symptoms commonly include headache (85%) and fatigue (66%); visual changes are uncommon 2
• Central hypothyroidism is most commonly seen (>90%), followed by central adrenal insufficiency 2
• Both central hypothyroidism and adrenal insufficiency occur in >75% of patients 2

Immediately evaluate for concurrent adrenal insufficiency with 9 AM cortisol, as steroids must be started before thyroid hormone replacement to prevent adrenal crisis 1, 2.

Diagnostic Workup for Suspected Hypophysitis

All patients with suspected hypophysitis should undergo further testing for diagnostic confirmation 2. Recommended tests, preferably conducted in the morning around 8 am, include:

• Thyroid function (TSH, free T4) 2
• Adrenal function (ACTH, cortisol or 1 mcg cosyntropin stimulation test) 2
• Gonadal hormones (testosterone in men, estradiol in women) 2
• FSH, LH 2
• MRI of the sella, with pituitary cuts 2

This should be done prior to administration of steroids 2.

Treatment of Confirmed Hypophysitis

Management of confirmed hypophysitis includes replacement of deficient hormones (physiologic doses of steroids and thyroid hormone) 2. In the presence of both adrenal insufficiency and hypothyroidism, steroids should always be started prior to thyroid hormone in order to avoid an adrenal crisis 2.

• High doses of steroids are necessary in the setting of severe headaches, vision changes or adrenal crisis 2
• Both adrenal insufficiency and hypothyroidism appear to represent long term sequelae of hypophysitis and lifelong hormonal replacement is needed in most cases 2
• All patients with adrenal insufficiency should be instructed to obtain and carry a medical alert bracelet 2

Risk Stratification for Primary Subclinical Hyperthyroidism

TSH <0.1 mIU/L (Grade II Subclinical Hyperthyroidism) carries substantial morbidity risk, including increased atrial fibrillation risk, bone demineralization, and cardiovascular mortality, and warrants intervention 1.

If on levothyroxine without indication for TSH suppression, reduce dose by 25-50 mcg immediately, and recheck TSH and free T4 in 6-8 weeks after dose adjustment 1.

Monitoring Strategy

After any intervention or in watchful waiting, recheck TSH and free T4 in 6-8 weeks (or 2 weeks for high-risk cardiac patients) 1. Once stable, monitor every 6-12 months or with symptom changes 1.

Target TSH for patients on levothyroxine replacement: 0.5-4.5 mIU/L 1.

Common Pitfalls to Avoid

• Never assume this is primary hyperthyroidism without checking medication history and clinical context 1
• Never start thyroid hormone replacement before ruling out adrenal insufficiency in suspected central hypothyroidism 2, 1
• Do not overlook immune checkpoint inhibitor-induced thyroiditis, which typically progresses from hyperthyroid to hypothyroid phase 1
• Failing to recognize that normal T4 with low TSH can represent central hypothyroidism rather than hyperthyroidism 2, 1