Low TSH with High T4: Primary Hyperthyroidism or Thyrotoxicosis
When TSH is low and T4 is high, this indicates thyrotoxicosis—a state of excess thyroid hormone that suppresses pituitary TSH secretion. This pattern represents either primary hyperthyroidism (Graves' disease, toxic nodular goiter) or destructive thyroiditis, and requires immediate evaluation to determine the underlying cause and guide treatment 1.
Pathophysiology and Clinical Significance
The combination of low/suppressed TSH with elevated free T4 or total T3 represents thyrotoxicosis, where excess thyroid hormone suppresses the pituitary's TSH production through negative feedback 1.
This pattern is fundamentally different from primary hypothyroidism (high TSH, low T4) and indicates the thyroid is producing or releasing excessive hormone 1.
Thyrotoxicosis due to thyroiditis is the most common cause in patients on immune checkpoint inhibitors, occurring more frequently with anti-PD1/PD-L1 drugs than anti-CTLA-4 agents 1.
Differential Diagnosis: Critical Distinctions
Destructive Thyroiditis (Most Common)
Painless thyroiditis presents with low/normal TSH and high free T4 or T3, typically occurring an average of one month after starting immunotherapy 1.
Patients may be asymptomatic or present with weight loss, palpitations, heat intolerance, tremors, anxiety, and diarrhea, though symptoms may be masked if taking beta-blockers 1.
This is a self-limiting process that leads to permanent hypothyroidism after an average of 1 month following the thyrotoxic phase 1.
Graves' Disease (Rare)
Graves' disease is very rare with immunotherapy and occurs more commonly with anti-CTLA-4 drugs 1.
Requires measurement of thyroid stimulating hormone receptor antibody (TRAb) or thyroid stimulating immunoglobulin (TSI) to distinguish from thyroiditis 1.
Non-Thyroidal Illness Syndrome
In hospitalized patients, the combination of low TSH and high FT4 is usually caused by non-thyroidal illness combined with drug effects, particularly when FT3 is below the middle of the normal range 2.
This pattern is common in hospitalized patients with infectious diseases (20.3% of cases) and typically does not require treatment if FT3 is low-normal 2.
Diagnostic Workup Algorithm
Step 1: Confirm the diagnosis with repeat testing
Measure TSH, free T4, and free T3 to establish the pattern and severity 1.
Check thyroid peroxidase (TPO) antibodies to evaluate for autoimmune thyroid disease 1.
Step 2: Distinguish thyroiditis from Graves' disease
Measure TRAb or TSI antibodies—positive results indicate Graves' disease 1.
Consider radioactive iodine uptake scan (RAIUS) or Technetium-99m thyroid scan if recent iodinated contrast was not used 1.
Low or absent uptake indicates thyroiditis; high uptake indicates Graves' disease or toxic nodular goiter 1.
Step 3: Evaluate clinical context
Review medication history, particularly recent initiation of immune checkpoint inhibitors 1.
Assess for symptoms of hypermetabolic activity: weight loss, palpitations, heat intolerance, tremors, anxiety, diarrhea 1.
In hospitalized patients with infectious disease, consider non-thyroidal illness syndrome, especially if FT3 is low-normal 2.
Management Based on Etiology
Thyroiditis Management (Conservative Approach)
Conservative management during the thyrotoxic phase is sufficient—no antithyroid drugs are needed 1.
Non-selective beta blockers, preferably with alpha receptor-blocking capacity, may be needed for symptomatic patients to control heart rate, tremor, and anxiety 1.
Repeat thyroid hormone levels every 2-3 weeks to monitor for transition to hypothyroidism 1.
Initiate thyroid hormone replacement at the time of hypothyroidism diagnosis, which typically occurs 1 month after the thyrotoxic phase and 2 months from immunotherapy initiation 1.
Graves' Disease Management
Requires antithyroid medications (methimazole or propylthiouracil), radioactive iodine, or thyroidectomy 1.
Refer to endocrinology for definitive management 1.
Non-Thyroidal Illness Syndrome
Treatment is probably unnecessary if FT3 level is below the middle of the normal range in hospitalized patients 2.
Studies have demonstrated no discernible benefit of treatment with T4 in non-thyroidal illness patients 3.
Focus on treating the underlying acute illness 3.
Critical Pitfalls to Avoid
Never start antithyroid drugs for thyroiditis—this is a self-limiting destructive process, not true hyperthyroidism, and antithyroid medications will not help 1.
Do not miss the transition to hypothyroidism—failure to monitor every 2-3 weeks during the thyrotoxic phase may result in delayed diagnosis of subsequent hypothyroidism 1.
In patients with both adrenal insufficiency and hypothyroidism, always start steroids prior to thyroid hormone to avoid precipitating adrenal crisis 1.
Avoid treating non-thyroidal illness syndrome with thyroid hormone in hospitalized patients, as this provides no benefit and may cause harm 2, 3.
When to Refer to Endocrinology
An endocrinology consultation is recommended in all cases of suspected or confirmed hyperthyroidism, hyperthyroidism, or thyroiditis 1.
Immediate referral is warranted if Graves' disease is confirmed or if the clinical picture is unclear 1.
Consider referral for hospitalized patients with persistent thyrotoxicosis despite conservative management 1.
Special Considerations
For patients on immune checkpoint inhibitors, continue immunotherapy in most cases—high-dose corticosteroids are rarely required for thyroid dysfunction 4.
Monitor TSH every 4-6 weeks as part of routine clinical monitoring for asymptomatic patients on immunotherapy 4.
Prolonged TSH suppression (<0.1 mIU/L) increases risk for atrial fibrillation, especially in elderly patients, and potential cardiovascular mortality 4.
For patients with known nodular thyroid disease, be cautious with iodine exposure (e.g., radiographic contrast agents) as this may exacerbate hyperthyroidism 4.