Low T3 and T4 with Normal TSH: Diagnostic Approach

Most Likely Diagnosis: Nonthyroidal Illness Syndrome (Euthyroid Sick Syndrome)

The combination of low T3, low T4, and normal (or low-normal) TSH in a hospitalized or acutely ill patient almost always represents nonthyroidal illness syndrome (NTIS), not true hypothyroidism. This pattern reflects an adaptive physiologic response to acute illness, starvation, or critical illness—not primary thyroid failure 1, 2, 3.

Key Diagnostic Algorithm

Step 1: Assess Clinical Context

Acute or chronic systemic illness present? Up to 70% of hospitalized patients with nonthyroidal disease show low serum T3, and in severe illness, T4 also falls while TSH remains normal or low-normal 1, 3.
Medications that suppress thyroid axis: Glucocorticoids, dopamine, and dobutamine directly suppress TSH and peripheral thyroid hormone levels 4.
Critical illness or ICU admission? The more severe the illness, the lower the T4 and T3, with mortality inversely correlated to serum T4 concentration 2, 5.

Step 2: Measure TSH to Differentiate Causes

Normal or low-normal TSH + low T3/T4 = Nonthyroidal illness syndrome 1, 2, 3
- TSH remains normal or slightly suppressed because the hypothalamic-pituitary axis senses adequate free T4 (despite low total T4) 1, 2
- Free T4 by equilibrium dialysis is often normal or only mildly reduced 2
Low or inappropriately normal TSH + low T3/T4 = Central hypothyroidism 4
- Hypophysitis (especially in patients on immune checkpoint inhibitors) causes low T4 with low/normal TSH, then low T3 4
- Central hypothyroidism produces low-normal free T4 (not high-normal), distinguishing it from subclinical hyperthyroidism 4
Markedly elevated TSH (>10 mIU/L) + low T3/T4 = Primary hypothyroidism 4
- Severe primary hypothyroidism eventually shows low T3 as well as low T4, but TSH is dramatically elevated 4

Step 3: Confirm with Additional Testing

Reverse T3 (rT3): Elevated rT3 argues against hypothyroidism and supports nonthyroidal illness 2
- However, rT3 is not reliable for distinguishing hypothyroid sick syndrome from euthyroid sick syndrome—normal or low rT3 can occur in either condition 6
- Drug effects and disease severity confound rT3 interpretation 6
Free T4 by equilibrium dialysis: Most accurate method in critically ill patients 2
- Standard free T4 assays are unreliable in severe illness 1
- If free T4 by dialysis is low with normal/low TSH, consider central hypothyroidism 2
Cortisol and ACTH: Always check if central hypothyroidism is suspected, as concurrent adrenal insufficiency is common and must be treated before thyroid hormone replacement to avoid adrenal crisis 4

Mechanisms of Nonthyroidal Illness Syndrome

Why T3 Falls First

Decreased peripheral conversion of T4 to T3 via inhibition of type 1 5'-deiodinase in liver and kidney 1, 5
Increased conversion to reverse T3 (rT3) instead of active T3 1, 5
Serum T3 drops to hypothyroid range (<90 ng/dL) in 70% of hospitalized patients despite clinical euthyroidism 3

Why T4 Falls in Severe Illness

Decreased thyroid hormone binding to serum proteins (TBG, albumin) due to circulating inhibitors and reduced protein synthesis 1
Impaired hepatic uptake and transport of thyroid hormones 5
Cytokine-mediated suppression of thyroid axis (IL-6, TNF-α) 5
Free T4 often remains normal despite low total T4 because the dialyzable fraction increases 1, 3

Why TSH Stays Normal

Altered TSH regulation in illness, but TSH remains within normal range in most patients 1, 3
Adequate free T4 sensed by pituitary prevents TSH elevation 1
TSH may be slightly elevated (mean 2.6 vs 1.9 µU/mL in controls) but not in the hypothyroid range 3
TRH response may be moderately exaggerated, but TSH levels do not reach those seen in primary hypothyroidism 3

Critical Management Pitfalls

Do NOT Treat Nonthyroidal Illness Syndrome with Thyroid Hormone

No benefit demonstrated: Multiple studies show no improvement in survival or clinical outcomes with T4 replacement in nonthyroidal illness 2, 5
Adaptive response: Low T3 is likely a protective mechanism to conserve protein during catabolic illness 1, 5
Patients appear clinically euthyroid despite low T3, supporting the adaptive nature of this response 1, 3

DO Treat Central Hypothyroidism—But Steroids First

If central hypothyroidism confirmed (low free T4 by dialysis + low/normal TSH + pituitary disease), thyroid hormone replacement is indicated 4, 2
Always start glucocorticoids first if concurrent adrenal insufficiency exists, to avoid precipitating adrenal crisis 4
Hypophysitis from immune checkpoint inhibitors requires physiologic thyroid hormone replacement after steroid coverage 4

Distinguish Primary Hypothyroidism from Nonthyroidal Illness

TSH >20-25 µU/mL strongly suggests primary hypothyroidism, especially with goiter, positive anti-TPO antibodies, and low free T4 2
Elevated rT3 argues against hypothyroidism (though not definitive) 2
In critically ill patients, none of the available free T4 methods may accurately reflect thyroid status—clinical judgment is essential 1

When to Recheck Thyroid Function

After recovery from acute illness: Repeat TSH and free T4 in 4-6 weeks after resolution of nonthyroidal illness 7
30-60% of abnormal thyroid tests normalize spontaneously after recovery from acute illness 7
If TSH remains elevated or free T4 remains low after recovery, then true hypothyroidism is likely and treatment is indicated 7

Summary: Practical Approach

Low T3/T4 + normal TSH in sick patient = Nonthyroidal illness syndrome until proven otherwise 1, 2, 3
Do not treat with thyroid hormone—no evidence of benefit 2, 5
Check free T4 by equilibrium dialysis and TSH to exclude central hypothyroidism 2
If central hypothyroidism suspected, rule out adrenal insufficiency first 4
Recheck thyroid function 4-6 weeks after recovery from acute illness 7
Elevated rT3 supports nonthyroidal illness but is not definitive 2, 6

What are the possible causes and appropriate work‑up for low serum triiodothyronine (T3) and thyroxine (T4) with a normal or low‑normal thyroid‑stimulating hormone (TSH)?

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