How do levels of Triiodothyronine (T3), Thyroxine (T4), and Thyroid-Stimulating Hormone (TSH) change in thyroid disorders?

Thyroid Hormone Changes in Thyroid Disorders

Primary Hypothyroidism

In primary hypothyroidism, TSH is elevated while T4 and T3 are decreased, with TSH being the most sensitive early indicator of thyroid gland failure. 1

Laboratory Pattern

• TSH is elevated (>4.5 mIU/L), often markedly so in overt disease, as the pituitary attempts to stimulate the failing thyroid gland 1
• Free T4 is low in overt hypothyroidism, but remains normal in subclinical hypothyroidism despite elevated TSH 2
• T3 levels decrease but typically fall later than T4, as peripheral conversion from T4 to T3 initially compensates 3
• The T3/T4 ratio increases to 24.12 in untreated hypothyroidism (compared to 15.89 in euthyroid individuals), reflecting the body's attempt to maintain T3 levels through enhanced peripheral conversion 4

Subclinical vs. Overt Hypothyroidism

• Subclinical hypothyroidism is defined as elevated TSH (typically >4.5 mIU/L) with normal free T4 levels 2
• Overt hypothyroidism shows both elevated TSH and low free T4 2
• TSH >10 mIU/L carries approximately 5% annual risk of progression to overt hypothyroidism 2

Important Caveats

• TSH elevation precedes T4 abnormalities in the evolution of hypothyroidism, making TSH the earliest and most sensitive marker 5
• Serial TSH measurements are essential, as 30-60% of elevated TSH values normalize spontaneously on repeat testing 1
• TSH can vary by up to 50% day-to-day in the same individual, and is affected by acute illness, medications (dopamine, glucocorticoids, iodine), pregnancy, and other conditions 1

Primary Hyperthyroidism

In hyperthyroidism, TSH is suppressed or undetectable while T4 and T3 are elevated, with T3 often rising disproportionately higher than T4. 3

Laboratory Pattern

• TSH is suppressed (<0.1-0.4 mIU/L) due to negative feedback from excess thyroid hormones on the pituitary 6
• Free T4 is elevated in most cases of hyperthyroidism 3
• T3 is elevated, often more dramatically than T4, reflecting increased thyroid secretion and peripheral conversion 3
• The T3/T4 ratio increases to 19.57 in hyperthyroidism (compared to 15.89 in euthyroid state) 4

T3 Thyrotoxicosis

• Approximately 5% of hyperthyroid patients have selective T3 elevation with normal T4, termed "T3 thyrotoxicosis" 3
• This pattern requires measuring both T3 and T4 to avoid missing the diagnosis 3

Distinguishing Hyperthyroidism from Thyroiditis

• T3/T4 ratio >18.9 suggests Graves' disease or toxic multinodular goiter 4
• T3/T4 ratio <16 suggests thyroiditis (subacute or silent), as in De Quervain's thyroiditis where the ratio averages 15.16 4
• In subacute thyroiditis, the T3/T4 ratio remains comparable to euthyroid individuals despite thyrotoxic symptoms 4

Central (Secondary/Tertiary) Hypothyroidism

In central hypothyroidism from pituitary or hypothalamic dysfunction, TSH is low or inappropriately normal despite low T4, making TSH unreliable as a screening test. 2

Laboratory Pattern

• TSH is low or inappropriately normal (not elevated as expected), because the pituitary fails to produce adequate TSH or the hypothalamus fails to produce TRH 2
• Free T4 is low, confirming hypothyroidism despite the misleading TSH 2
• T3 may be low or normal depending on peripheral conversion 2

Critical Diagnostic Approach

• Always check free T4 alongside TSH in patients with pituitary disease or symptoms despite normal TSH 2
• Never rely on TSH alone in suspected central hypothyroidism 2
• Before initiating levothyroxine, rule out concurrent adrenal insufficiency, as starting thyroid hormone before corticosteroids can precipitate adrenal crisis 2

Thyroid Hormone Replacement Effects

Patients on levothyroxine replacement have lower T3 levels and lower T3/T4 ratios than normal individuals with the same TSH, suggesting TSH may not fully reflect tissue thyroid status. 7, 4

Laboratory Pattern on Levothyroxine

• TSH normalizes (target 0.5-4.5 mIU/L) with adequate replacement 2
• T4 levels are higher than in untreated euthyroid individuals (9.11 vs 7.99 μg/dL) to achieve normal TSH 4
• T3 levels remain lower than in euthyroid controls despite normal TSH, indicating relative tissue hypothyroidism 7, 4
• The T3/T4 ratio decreases to 13.42 in treated hypothyroidism (compared to 15.89 in natural euthyroid state), reflecting dependence on peripheral T4-to-T3 conversion rather than direct thyroid T3 secretion 4
• SHBG levels are lower in treated hypothyroid patients compared to euthyroid controls with the same TSH, suggesting relative hepatic hypothyroidism 7

Clinical Implications

• TSH levels used to monitor replacement are regulated by intracellular T3 in the pituitary and may not indicate adequate thyroid hormone action in all tissues 7
• The narrow individual variation in T3 and T4 (coefficient of variation <10%) means each patient has their own optimal levels that may differ from population reference ranges 8
• Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, increasing risks for atrial fibrillation, osteoporosis, and cardiac complications 2

Monitoring Requirements

• Monitor TSH every 6-8 weeks during dose titration 2
• Once stable, recheck TSH every 6-12 months 2
• Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize 2
• Development of TSH <0.1 mIU/L indicates overtreatment requiring dose reduction 2