Thyroid Serie Article 3: From T4 to T3 — The Metabolic Messengers and Their Cellular Journey

Once your thyroid gland has produced the hormones T4 and T3, the job is only half done. These hormones must now travel through your bloodstream, reach target tissues, enter your cells, and be converted into their active or inactive forms.

This step is critical — because the majority of what your thyroid releases is T4, a mostly inactive prohormone. The real action happens in the tissues, where T4 is converted to either:

  • T3 (Triiodothyronine) — the active form

  • rT3 (Reverse T3) — the inactive "brake"

Let’s dive into this powerful and finely-tuned conversion system — and how your genes, stress levels, and nutrition all affect the outcome.

🔄 T4 Conversion: A Balancing Act Between T3 and rT3

Inside cells (in the liver, brain, muscles, thyroid, and other tissues), thyroid hormones are activated or deactivated by enzymes called deiodinases (DIOs). These remove iodine atoms from T4 to produce T3 or rT3.

🧬 The Three Deiodinases:

  1. DIO1 (Deiodinase Type 1)

    • Activates T4 → T3

    • Also deactivates rT3 → T2

    • Highly expressed in the thyroid, liver, kidneys

    • SNP rs2235544: associated with lower DIO1 activity, leading to higher rT3, lower T3, and symptoms like fatigue, weight gain, and depression

  2. DIO2 (Deiodinase Type 2)

    • Main local activator of T4 → T3 in tissues (especially brain and thyroid)

    • Works in the endoplasmic reticulum so T3 can directly access the cell nucleus

    • SNPs like Thr92Ala and Gly3Asp are associated with:

      • Lower DIO2 expression

      • Local hypothyroidism (even when blood T4 looks “normal”)

      • Fatigue, low mood, and cognitive issues

  3. DIO3 (Deiodinase Type 3)

    • Deactivates T4 → rT3 and T3 → T2

    • Normally active in pregnancy and development, but reactivated by:

      • Chronic stress

      • Inflammation

      • Caloric restriction/starvation

    • Result: high rT3, leading to a hypometabolic state (like burnout or hibernation)

📌 Key point: DIO1 and DIO2 activate; DIO3 inactivates. Balance between these determines your thyroid hormone signaling power.

🧬 Genetic SNPs and Their Impact

👉 DIO1 (rs2235544)

  • Lower activity = lower T3, higher rT3

  • Often seen in depression, fatigue, poor weight regulation

👉 DIO2 (Thr92Ala, Gly3Asp)

  • Linked to bipolar disorder, chronic fatigue, hypothyroid symptoms

  • Despite “normal” TSH or T4 labs, the brain may be starving for T3

👉 DIO3 upregulation

  • Not a SNP, but often seen in critical illness, fasting, or overtraining

  • Leads to increased rT3 (which blocks T3 at the receptor)

⚙️ Transport Into the Cells — The SLCO Genes

Thyroid hormones don’t just float into cells. They require specialized transport proteins:

  • SLCO1C1: Transports T4 and rT3 into the brain

    • SNP rs10770704: linked to reduced transport, brain fog, fatigue

  • SLCO1B1: Found in the liver

    • SNP V174A: reduces hormone clearance, increasing risk of side effects from medications like statins, and interfering with T4 deactivation (T4S)

These transporters ensure the right hormones get to the right tissues at the right time.

🧬 Nutritional Support for Conversion

Proper T4-to-T3 conversion depends on:

  • Selenium: cofactor for all DIO enzymes and glutathione peroxidase (protects thyroid from H₂O₂ damage)

  • Zinc: important for DIO activity and thyroid receptor sensitivity

  • Iodine: required for T4, but too much inhibits DIO1 and increases rT3

  • Antioxidants (Glutathione, Vitamin C, A, E): protect against oxidative stress that impairs deiodinases

💥 What Can Block Conversion?

These factors increase rT3 and decrease T3 production:

  • Chronic stress / high cortisol

  • Inflammation / infections

  • Fasting / extreme caloric restriction

  • Toxicity (e.g. mercury, pesticides)

  • Low selenium or zinc

  • Genetic SNPs on DIO1/DIO2

🧠 Clinical Symptoms of Poor Conversion

When you produce enough T4, but can’t convert it into T3 (or make too much rT3), you may experience:

  • Brain fog, anxiety, low mood

  • Cold hands and feet

  • Hair loss, dry skin

  • Low heart rate, fatigue

  • Poor response to T4 medication

This is often called “cellular hypothyroidism”, even when lab values seem “normal.”

🔎 Functional Lab Clues

  • High rT3

  • Low-normal T3 or Free T3

  • TSH and T4 may appear normal

That’s why it’s essential to test T3 and rT3, not just TSH.

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