What are the causes of low Triiodothyronine (T3) levels?

Causes of Low T3 Levels

Low T3 levels most commonly result from nonthyroidal illness syndrome (sick euthyroid syndrome), where decreased peripheral conversion of T4 to T3 occurs as an adaptive response to systemic illness, rather than from intrinsic thyroid disease. 1, 2

Primary Causes

Nonthyroidal Illness Syndrome (Most Common)

• Acute and chronic systemic illnesses cause decreased T3 production through reduced activity of type-1 deiodinase enzyme, which converts T4 to T3 1, 2
• The severity correlates with illness severity—mild illness causes isolated low T3, while severe/prolonged illness causes both low T3 and low T4 1, 3
• Critical illness produces the most pronounced changes, with suppressed hypothalamic TRH expression in prolonged cases leading to reduced TSH and further thyroid hormone decline 1
• TSH typically remains normal or low-normal in nonthyroidal illness, distinguishing it from primary hypothyroidism 2, 3

Nutritional Causes

• Caloric deprivation and starvation decrease T3 production through the same mechanisms as nonthyroidal illness—reduced 5'-deiodinase activity 4
• This represents an adaptive mechanism to conserve energy and decrease protein breakdown 4

Medication-Induced Low T3

• Amiodarone inhibits peripheral conversion of T4 to T3, causing decreased T3 levels with increased T4 and reverse T3 in clinically euthyroid patients 5
• Glucocorticoids, dopamine, and dobutamine can suppress thyroid axis function 6

Central (Hypothalamic-Pituitary) Dysfunction

• Hypophysitis (particularly immune checkpoint inhibitor-induced) causes low T4 with low/normal TSH, and subsequently low T3 7
• Requires ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) combined with MRI abnormality, or ≥2 hormone deficiencies with symptoms 7
• Central hypothyroidism from any cause produces low-normal free T4 rather than high-normal, distinguishing it from subclinical hyperthyroidism 6

Primary Hypothyroidism (Late Stage)

• While primary hypothyroidism initially presents with high TSH and low T4, severe cases eventually show low T3 as well 7
• Distinguished by markedly elevated TSH (typically >10 mIU/L) 7

Key Diagnostic Distinctions

Laboratory Pattern Recognition

• Low T3 with normal TSH and normal/high T4: Nonthyroidal illness or amiodarone effect 5, 2
• Low T3 with low T4 and low/normal TSH: Severe nonthyroidal illness or central hypothyroidism 7, 1
• Low T3 with low T4 and high TSH: Primary hypothyroidism 7
• Increased reverse T3: Strongly suggests nonthyroidal illness rather than true hypothyroidism 1, 2

Clinical Context Matters

• Hospitalized/critically ill patients: Assume nonthyroidal illness syndrome until proven otherwise 1, 3
• Patients on immune checkpoint inhibitors: Consider hypophysitis if headache, fatigue, or other pituitary symptoms present 7
• Patients on amiodarone: Expect altered thyroid parameters as a pharmacologic effect 5

Critical Management Pitfall

Do not treat isolated low T3 in the setting of nonthyroidal illness with thyroid hormone replacement—this represents an adaptive, beneficial response to conserve energy and protein, and treatment has not been shown to improve outcomes 2, 3, 4. The low T3 normalizes with resolution of the underlying illness 3.

The exception is confirmed central hypothyroidism from hypophysitis or other pituitary disease, which requires physiologic thyroid hormone replacement (but always start steroids first if concurrent adrenal insufficiency exists to avoid precipitating adrenal crisis) 7.