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Quick Reference
  • Normal Range: 0.4-4.0 mIU/L (narrower optimal range 0.5-2.5 mIU/L for treatment targets)
  • Critical High: >10 mIU/L (overt hypothyroidism likely)
  • Critical Low: <0.1 mIU/L (overt hyperthyroidism or thyrotoxicosis)
  • Primary Use: Best single screening test for thyroid dysfunction; monitoring levothyroxine dose
  • Sample Type: Serum (morning preferred for consistency)
  • Key Point: TSH lags behind thyroid hormone changes - wait 6-8 weeks after dose adjustment before rechecking

Test Description

What is TSH?

Thyroid-Stimulating Hormone (TSH), also called thyrotropin, is a glycoprotein hormone produced by thyrotroph cells in the anterior pituitary gland. TSH regulates thyroid hormone production through the hypothalamic-pituitary-thyroid (HPT) axis.

The HPT Axis - Negative Feedback Loop

Understanding the HPT axis is essential for interpreting thyroid function tests:

  • Hypothalamus: Releases TRH (thyrotropin-releasing hormone) in response to low thyroid hormone levels or cold exposure
  • Pituitary: TRH stimulates anterior pituitary thyrotrophs to release TSH into bloodstream
  • Thyroid gland: TSH binds to TSH receptors on thyroid follicular cells, stimulating production and release of T4 and T3
  • Negative feedback: Rising T4 and T3 levels suppress TRH and TSH production, completing the regulatory loop
Inverse Relationship: TSH has an inverse log-linear relationship with Free T4. Small changes in thyroid hormone levels cause large reciprocal changes in TSH. This amplification makes TSH the most sensitive screening test for thyroid dysfunction - abnormal TSH often appears before Free T4 leaves the normal range.

How Does TSH Work?

TSH regulates multiple aspects of thyroid function:

  • Hormone synthesis: Stimulates iodine uptake, thyroglobulin synthesis, and thyroid hormone production
  • Hormone release: Promotes release of stored T4 and T3 from thyroid follicles
  • Gland growth: Chronic TSH elevation causes thyroid hypertrophy (goiter formation)
  • Blood flow: Increases thyroid gland vascularity and metabolic activity

Why is TSH the Best Screening Test?

TSH is the single most useful test for detecting thyroid dysfunction:

  • High sensitivity: Detects subclinical disease before symptoms or Free T4 abnormalities appear
  • Wide dynamic range: TSH varies over 100-fold range while Free T4 changes minimally
  • Standardized assay: Third-generation TSH assays are highly accurate and reproducible
  • Cost-effective: Single test screens for both hypo- and hyperthyroidism
Normal Ranges

TSH reference ranges vary by age, pregnancy status, and clinical context. The "normal" range debate continues regarding optimal targets for treatment.

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Population TSH Range (mIU/L) Notes
Adults (general) 0.4-4.0 Standard reference range; some labs use 0.5-5.0
Optimal treatment target 0.5-2.5 Narrower range preferred for levothyroxine-treated patients
Pregnancy - 1st trimester 0.1-2.5 Lower TSH normal due to hCG cross-reactivity
Pregnancy - 2nd trimester 0.2-3.0 TSH gradually rises as pregnancy progresses
Pregnancy - 3rd trimester 0.3-3.0 Approaches non-pregnant normal by term
Elderly (>80 years) 0.4-6.0 Upper limit may be higher; treat based on symptoms
Newborns (1-4 days) 1.0-20.0 Physiologic TSH surge after birth
Pregnancy-Specific TSH Targets: TSH should be <2.5 mIU/L in first trimester and <3.0 mIU/L in second/third trimesters for optimal fetal neurodevelopment. Levothyroxine dose typically increases 30-50% during pregnancy due to increased metabolic demands.
Important Considerations:
  • Assay variation: Different TSH assays may have different reference ranges; use lab-specific values
  • Time of day: TSH peaks at 2-4 AM and is lowest in afternoon; check at same time for serial monitoring
  • Treatment targets: ATA recommends TSH 0.5-2.5 mIU/L for levothyroxine-treated patients, though some tolerate wider ranges
  • Age adjustment: TSH reference range increases with age; elderly may tolerate TSH 4-6 mIU/L without symptoms
Clinical Significance

Elevated TSH (Hypothyroidism)

Elevated TSH indicates inadequate thyroid hormone production. The pituitary increases TSH to stimulate more T4/T3 release.

Primary Hypothyroidism (High TSH, Low/Normal Free T4)

  • Hashimoto's thyroiditis: Most common cause; autoimmune destruction of thyroid (anti-TPO and anti-thyroglobulin antibodies positive)
  • Iatrogenic: Post-radioactive iodine ablation, post-thyroidectomy, external beam radiation to neck
  • Iodine deficiency: Still common worldwide; rare in iodine-supplemented regions
  • Medications: Lithium, amiodarone, interferon-alpha, tyrosine kinase inhibitors, immune checkpoint inhibitors
  • Congenital hypothyroidism: Thyroid dysgenesis, dyshormonogenesis; detected by newborn screening
  • Subacute thyroiditis: Transient hypothyroidism after initial hyperthyroid phase (painful thyroid, elevated ESR)
  • Postpartum thyroiditis: Occurs 1-6 months postpartum; often transient but may become permanent

Subclinical Hypothyroidism (TSH 4.5-10 mIU/L, Normal Free T4)

  • Definition: Elevated TSH with normal Free T4; often asymptomatic or minimal symptoms
  • Progression risk: 2-5% annually progress to overt hypothyroidism, especially if anti-TPO antibodies positive
  • Treatment controversy: Treatment debated for TSH 4.5-10; most experts treat if TSH >10, pregnant, or symptomatic
  • Risk factors: Positive TPO antibodies, goiter, symptoms, pregnancy planning increase treatment likelihood

Low TSH (Hyperthyroidism)

Suppressed TSH indicates excess thyroid hormone. Negative feedback from high T4/T3 levels shuts down TSH production.

Primary Hyperthyroidism (Low TSH, High Free T4/T3)

  • Graves' disease: Most common cause; autoimmune with TSH receptor-stimulating antibodies (TSI/TRAb positive)
  • Toxic multinodular goiter: Autonomous nodules producing excess hormone independent of TSH
  • Toxic adenoma: Single autonomously functioning thyroid nodule
  • Thyroiditis (early phase): Subacute (de Quervain's), postpartum, or painless lymphocytic thyroiditis
  • Exogenous thyroid hormone: Excessive levothyroxine dose, intentional or factitious hyperthyroidism
  • Iodine-induced (Jod-Basedow): Hyperthyroidism triggered by iodine exposure (contrast, amiodarone) in iodine-deficient patients
  • hCG-mediated: Molar pregnancy, hyperemesis gravidarum (hCG has weak TSH-like activity)

Subclinical Hyperthyroidism (TSH <0.4 mIU/L, Normal Free T4/T3)

  • Definition: Suppressed TSH with normal thyroid hormones; may be asymptomatic
  • Severity classification: Mild (TSH 0.1-0.4) vs. severe (TSH <0.1); severe has higher risk of complications
  • Risks: Atrial fibrillation, osteoporosis, increased mortality (especially if TSH <0.1 and age >65)
  • Treatment indications: Consider treatment if TSH <0.1, age >65, cardiac disease, or osteoporosis

Central (Secondary/Tertiary) Hypothyroidism

Rare condition where pituitary or hypothalamus fails, causing low TSH AND low Free T4.

  • Pituitary adenoma: Mass effect on thyrotrophs or hypopituitarism
  • Pituitary surgery/radiation: Iatrogenic hypopituitarism
  • Sheehan syndrome: Postpartum pituitary necrosis from severe hemorrhage
  • Infiltrative disease: Sarcoidosis, hemochromatosis, histiocytosis X
  • TRH deficiency: Hypothalamic injury from tumor, trauma, or infiltration
  • Key feature: Low TSH + Low Free T4 (TSH not appropriately elevated despite hypothyroidism)
Interpretation Guidelines

TSH + Free T4 Interpretation Patterns

Always interpret TSH with Free T4 for complete diagnosis:

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TSH Free T4 Interpretation Common Causes
High Low Overt Primary Hypothyroidism Hashimoto's, post-RAI, iodine deficiency
High Normal Subclinical Hypothyroidism Early Hashimoto's, inadequate levothyroxine dose
Low High Overt Primary Hyperthyroidism Graves' disease, toxic nodular goiter
Low Normal Subclinical Hyperthyroidism Early Graves', autonomous nodule, excess levothyroxine
Low Low Central Hypothyroidism Pituitary adenoma, hypopituitarism, Sheehan syndrome
Normal Normal Euthyroid (Normal Thyroid Function) Healthy state
When to Add Free T3: TSH and Free T4 are usually sufficient. Order Free T3 when:
  • Hyperthyroidism with normal Free T4 (possible T3 toxicosis)
  • Monitoring treatment of Graves' disease
  • Suspected thyrotoxicosis with confusing TSH/T4 pattern

Subclinical Disease Management

Subclinical Hypothyroidism (TSH 4.5-10 mIU/L, Normal Free T4)

Treatment Guidelines (ATA/AACE):
  • TSH >10 mIU/L: Treat with levothyroxine (consensus recommendation)
  • TSH 4.5-10 mIU/L: Treatment controversial; consider if:
    • Positive anti-TPO antibodies (high progression risk)
    • Symptomatic (fatigue, weight gain, cold intolerance)
    • Goiter present
    • Pregnancy or planning pregnancy (target TSH <2.5)
    • Young age (<30 years) with high progression likelihood
  • If not treating: Recheck TSH and Free T4 every 6-12 months to monitor for progression

Subclinical Hyperthyroidism (TSH <0.4 mIU/L, Normal Free T4/T3)

Treatment Considerations:
  • TSH <0.1 mIU/L: Higher risk; consider treatment especially if:
    • Age >65 years (AF and osteoporosis risk)
    • Cardiac disease (can precipitate AF or heart failure)
    • Osteoporosis or high fracture risk
  • TSH 0.1-0.4 mIU/L: Lower risk; monitor without treatment unless symptomatic
  • Exogenous cause: If due to excess levothyroxine, reduce dose

Levothyroxine Dose Adjustment

TSH-guided levothyroxine dosing requires patience and proper timing:

Dosing Principles:
  • Wait 6-8 weeks: TSH lags behind Free T4 changes; requires 6-8 weeks to reach new steady state after dose change
  • Initial dose: 1.6 mcg/kg/day for young healthy adults; lower (25-50 mcg/day) for elderly or cardiac disease
  • Dose adjustments: Change by 12.5-25 mcg increments; recheck TSH 6-8 weeks after each change
  • Target TSH: 0.5-2.5 mIU/L for most patients; individualize based on age and symptoms
  • Consistency: Take levothyroxine on empty stomach 30-60 minutes before breakfast; avoid with calcium, iron, PPIs
Common Dosing Mistakes:
  • Checking TSH too soon: Must wait 6-8 weeks; earlier testing shows incomplete response
  • Frequent dose changes: Leads to oscillating TSH; make one change and wait
  • Over-suppression: TSH <0.1 increases AF and osteoporosis risk; avoid unless treating thyroid cancer
  • Ignoring medication interactions: PPIs, calcium, iron, estrogen, bile acid sequestrants affect absorption
Interfering Factors

Factors That Increase TSH

  • Medications: Lithium, amiodarone (type 2), interferon-alpha, metoclopramide, domperidone, immune checkpoint inhibitors (nivolumab, pembrolizumab)
  • Thyroid hormone resistance: Genetic defect requiring high TSH to maintain normal T4/T3
  • TSH-secreting pituitary adenoma: Rare; high TSH + high Free T4/T3 (not suppressed)
  • Recovery from non-thyroidal illness: TSH may transiently elevate during recovery phase
  • Assay interference: Heterophile antibodies, macro-TSH (immunoglobulin-bound TSH)

Factors That Decrease TSH

  • Medications: Glucocorticoids (high dose), dopamine, dobutamine, metformin, opioids (chronic use), somatostatin analogs
  • First trimester pregnancy: hCG has weak TSH-like activity; suppresses TSH physiologically
  • Non-thyroidal illness (sick euthyroid syndrome): Critical illness suppresses TSH; low T3, low/normal T4, low/normal TSH
  • Assay interference: Biotin supplementation (high dose >5 mg/day) can falsely lower TSH in some immunoassays

Diurnal Variation

TSH follows circadian rhythm with important clinical implications:

  • Peak: 2-4 AM (TSH highest during sleep)
  • Nadir: 2-6 PM (TSH lowest in afternoon/evening)
  • Variation magnitude: TSH can vary 50-100% throughout day in same individual
  • Clinical impact: Draw TSH at same time of day for serial monitoring; morning preferred for consistency

Non-Thyroidal Illness (Sick Euthyroid Syndrome)

Critical illness profoundly affects thyroid function tests without true thyroid disease:

  • Pattern: Low T3 (most common), low/normal T4, low/normal TSH during acute illness
  • Mechanism: Decreased peripheral T4-to-T3 conversion; adaptive response to conserve energy
  • Management: Do NOT treat with thyroid hormone; recheck after illness resolves
  • Recovery: TSH may transiently elevate during recovery phase (can mimic hypothyroidism)

Biotin Interference

High-dose biotin supplementation can cause false TSH results:

  • Mechanism: Many TSH assays use biotin-streptavidin immunoassays; excess biotin interferes
  • Dose threshold: >5 mg/day (much higher than RDA 30 mcg); supplements often contain 5-10 mg
  • Effect: Falsely low TSH, falsely high Free T4/T3 (mimics hyperthyroidism)
  • Prevention: Discontinue biotin 48-72 hours before thyroid testing
Clinical Pearls
Clinical Pearl
"TSH lags 6-8 weeks behind T4 changes": After changing levothyroxine dose, TSH requires 6-8 weeks to reach new steady state. Checking TSH earlier gives misleading results. Conversely, Free T4 changes within 2 weeks but doesn't reflect pituitary adjustment.
Clinical Pearl
"TSH is the amplifier": Small changes in Free T4 (10-20%) cause large reciprocal TSH changes (50-100%). This log-linear inverse relationship makes TSH far more sensitive than Free T4 for detecting subclinical disease.
Euthyroid sick syndrome - DO NOT TREAT: Critical illness causes low T3, low/normal T4, and low/normal TSH without true hypothyroidism. This is an adaptive response. Treating with thyroid hormone increases mortality. Recheck 6-8 weeks after illness resolves.
Clinical Pearl
Pregnancy TSH targets are lower: First trimester TSH should be <2.5 mIU/L for optimal fetal neurodevelopment. Levothyroxine dose typically increases 30-50% during pregnancy. Check TSH every 4-6 weeks during pregnancy in hypothyroid women.
Subclinical hypothyroidism treatment thresholds: TSH >10 mIU/L - treat. TSH 4.5-10 mIU/L - treatment controversial; consider if positive TPO antibodies, symptomatic, pregnant, or goiter present. Otherwise, monitor every 6-12 months.
Clinical Pearl
"Low TSH + Low Free T4 = think pituitary": Primary hypothyroidism causes HIGH TSH. If both TSH and Free T4 are low, suspect central (secondary) hypothyroidism from pituitary failure. Check other pituitary hormones and obtain pituitary MRI.
Biotin interference is real: High-dose biotin (>5 mg/day in supplements) causes falsely low TSH and falsely high Free T4/T3, mimicking hyperthyroidism. Always ask about supplements. Stop biotin 48-72 hours before testing.
Clinical Pearl
Over-replacement increases AF and osteoporosis risk: TSH <0.1 mIU/L from excess levothyroxine increases atrial fibrillation and bone loss, especially in elderly. Target TSH 0.5-2.5 mIU/L unless treating thyroid cancer (where suppression is intentional).
Morning vs afternoon TSH differences: TSH peaks at 2-4 AM and is 50% lower by afternoon. For serial monitoring, check TSH at same time of day (morning preferred). A patient with morning TSH 3.5 may have afternoon TSH 2.5 - both normal but can cause confusion.
Clinical Pearl
"Take levothyroxine alone on empty stomach": PPIs, calcium, iron, bile acid sequestrants, and food reduce levothyroxine absorption by 20-50%. Take levothyroxine 30-60 minutes before breakfast or at bedtime (4 hours after dinner). Maintain consistency.
Clinical Pearl
TSH may rise with estrogen therapy: Oral estrogen (contraceptives, HRT) increases TBG, raising Total T4 but not Free T4. However, levothyroxine dose may need to increase by 25-30% due to increased protein binding reducing bioavailable T4.
Amiodarone thyroid effects are complex: Amiodarone causes both hypo- and hyperthyroidism. Type 1 (hyperthyroidism from iodine load) vs Type 2 (destructive thyroiditis). Check baseline TSH before starting amiodarone and every 3-6 months during therapy.
References
  1. Kratz, A., Ferraro, M., Sluss, P. M., & Lewandrowski, K. B. (2004). Laboratory reference values. New England Journal of Medicine, 351, 1548-1564.
  2. Lee, M. (Ed.). (2009). Basic skills in interpreting laboratory data. Ashp.
  3. Farinde, A. (2021). Lab values, normal adult: Laboratory reference ranges in healthy adults. Medscape. https://emedicine.medscape.com/article/2172316-overview?form=fpf
  4. Nickson, C. (n.d.). Critical Care Compendium. Life in the Fast Lane • LITFL. https://litfl.com/ccc-critical-care-compendium/
  5. Farkas, Josh MD. (2015). Table of Contents - EMCrit Project. EMCrit Project. https://emcrit.org/ibcc/toc/
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