Overview of #373 – Thyroid function and hypothyroidism (Peter Attia w/ Antonio Bianco, M.D., Ph.D.)
This episode is a deep dive into thyroid physiology, diagnostics, and treatment controversies with Dr. Antonio Bianco, a leading thyroid researcher and clinician. The conversation explains how thyroid hormone is produced, locally activated or inactivated by deiodinases, why relying on TSH alone misses important biology, why many patients remain symptomatic despite “normal” labs, and how newer approaches (combination therapy, better assays, slow‑release T3 formulations) could change care.
Key takeaways
- The thyroid secretes mostly T4 (pro‑hormone) and a small amount of T3 (active). Local conversion of T4 → T3 in tissues (by deiodinases) is how thyroid signaling is targeted and regulated.
- TSH + free T4 are the usual diagnostic anchors; T3 and reverse‑T3 (rT3) measurements are biologically informative but current immunoassays are unreliable (mass spectrometry is preferable when available).
- Deiodinases (D1, D2, D3) govern tissue‑level thyroid activity:
- D2: potent local activator (T4 → T3) — important in brain, brown fat, pituitary.
- D1: contributes to circulating T3 and clears rT3 (liver expression; insulin/carbohydrate sensitive).
- D3: inactivator (T3 → T2; T4 → rT3).
- Many patients feel unwell on levothyroxine (T4) despite normalized TSH; possible reasons include incomplete restoration of tissue T3, assay limitations, and comorbidities.
- Combination therapy (T4 + T3, synthetic or desiccated thyroid extract) shows patient preference in some studies and—per Dr. Bianco’s retrospective analyses—an association with lower mortality vs T4 monotherapy, but causality is uncertain.
- Major unmet needs: robust, CLIA‑grade mass spec assays for T3; validated slow‑release T3 formulations; better prospective clinical trials comparing regimens.
Physiology: what you need to understand
Thyroid hormone basics
- Thyroid gland concentrates iodine and synthesizes mainly T4 (tetra‑iodothyronine). T4 is long‑lived (≈8 days) but relatively inactive at nuclear receptors.
- T3 (triiodothyronine) is the active form (≈12 hour half‑life) that binds thyroid receptors with high affinity and regulates gene transcription.
Local control via deiodinases
- Deiodinases allow tissues to tune local T3 without large changes in circulating hormones.
- D2 (high affinity for T4): locally produces T3 (key in brain, brown adipose, pituitary).
- D1 (liver/kidney): produces some circulating T3 and clears rT3; sensitive to insulin/carbohydrate intake.
- D3: inactivates T3 and generates rT3 from T4 (important shut‑off pathway).
- Reverse T3 (rT3) is an inactive product; high rT3 can reflect increased inactivation and/or reduced clearance.
Hypothalamic–pituitary–thyroid (HPT) regulation
- Hypothalamus (TRH) → pituitary (TSH) → thyroid (T4/T3). Median eminence / some hypothalamic regions are outside the blood‑brain barrier and sense circulating thyroid hormones.
- Pituitary and hypothalamus have D2 activity to locally convert T4→T3 for feedback control.
Diagnostics: strengths, limitations, and assay issues
Typical lab panel and interpretation
- Most clinicians use TSH + free T4 for diagnosis. For primary hypothyroidism: high TSH + low free T4 (overt hypothyroidism).
- Subclinical hypothyroidism: elevated TSH with normal free T4.
- Central (secondary/tertiary) hypothyroidism: low/normal TSH with low free T4 → investigate pituitary/hypothalamus.
- TPO and thyroglobulin antibodies: markers of autoimmune thyroid disease (Hashimoto’s), but antibodies are not required to diagnose hypothyroidism.
Problems with T3 and rT3 assays
- Standard immunoassays: free T4 assay is generally reliable; total/free T3 and rT3 immunoassays are relatively poor and variable.
- Mass spectrometry (LC‑MS) provides much better accuracy for T3 (and would be preferable clinically), but CLIA‑approved mass spec T3 is not universally available.
- rT3 assays are especially unreliable between labs; rT3 can still be useful as a surrogate of deiodinase activity when interpreted carefully.
When TSH is misleading
- Non‑thyroidal illness, fasting, severe stress can alter peripheral deiodinase activity (e.g., fasting → lower T3, higher rT3, mildly increased TSH) — adaptive changes that complicate interpretation.
- Laboratory interference (heterophile antibodies / assay interference) can produce errant TSH values; consider assay recheck, alternate lab, or tests for antibody interference when results don’t match clinical picture.
- Age: normal TSH reference shifts upward with age; treatment thresholds differ in elderly patients.
Clinical scenarios and causes
Hypothyroidism
- Most common: autoimmune destruction (Hashimoto’s). Presents gradually; TPO antibodies often positive but not always.
- Other causes: thyroidectomy, radioactive iodine ablation, congenital defects, subacute thyroiditis, central hypothyroidism.
- Women much more affected than men (Dr. Bianco cites very large sex disparity).
Hyperthyroidism
- Main causes: Graves’ disease (TSH‑receptor stimulating antibody) and toxic nodules/multinodular goiter.
- Treatments: antithyroid drugs, surgery, radioactive iodine — choice depends on cause, age, comorbidities; evolving safety considerations around radioactive iodine.
Special contexts
- Pregnancy: iodine needs increase; TPO positivity raises miscarriage/prematurity risk even with normal thyroid labs — pregnancy is a scenario where closer thyroid surveillance is important.
- Fasting/illness: large shifts in peripheral T3/rT3 due to deiodinase changes (D1 down in liver when insulin/carbs are low → rT3 accumulates).
Treatment: options and controversies
Levothyroxine (T4) — standard of care
- Advantages: once‑daily dosing, long half‑life, stable formulations, widely used and guideline‑recommended.
- Limitations: in some patients it may not restore tissue‑level T3 sufficiently (liver and other tissues can remain relatively hypothyroid), and many patients have persistent symptoms despite normalized TSH.
T3 (liothyronine) and combination therapy
- T3 (immediate‑release, e.g., Cytomel): short half‑life → peaks and troughs; can cause symptoms of excess if dosing/timing poorly controlled.
- Combination synthetic T4+T3 and desiccated thyroid extract (DTE; pig thyroid) both provide T4 and T3. DTE has a roughly 3.5–4:1 T4:T3 ratio, close to physiologic thyroid secretion.
- Evidence: randomized blinded studies show some patient preference for combination therapy; Dr. Bianco reports retrospective data (propensity‑matched) suggesting lower mortality with combination vs T4 alone (~30% lower relative mortality in the matched cohort), but these are observational findings and not definitive proof of causality.
- Clinical approach: start with levothyroxine for most; consider combination therapy for patients with persistent symptoms after exclusion of other causes and after shared decision‑making.
Desiccated thyroid extract (DTE)
- Historically used; potency and stability were concerns but have improved since USP standards (1985) and mass‑spec potency checks.
- DTE is not FDA‑approved as a modern new drug (it predates current rules) but remains available; quality issues and recalls (like with many thyroid products) occur — choose reputable brands and monitor.
Compounding and slow‑release T3
- Compounded slow‑release T3: pharmacokinetic claims are largely unproven. Published testing has shown many compounded formulations do not have controlled release; quality and dose accuracy vary between compounding pharmacies.
- Industry progress: companies are developing slow‑release T3 (polymer‑based or sulfate prodrug approaches) that may provide physiologic steady T3 delivery — these are under investigation (early phase work), and would fill a major therapeutic gap if approved.
Controversies, gaps, and research priorities
- Overreliance on TSH alone: TSH is sensitive but not always sufficient, particularly for persistent symptoms, central hypothyroidism, or when tissue deiodination is altered.
- Poor T3 and rT3 assays limit clinical insight into tissue thyroid status; routine CLIA‑grade mass spec T3 would improve care.
- Evidence base: surprisingly few large prospective randomized trials comparing levothyroxine vs optimized combination therapy or slow‑release T3 exist; Dr. Bianco argues for better trials given observational signals.
- Need for validated slow‑release T3 formulations and clearer guidance for when to use combination therapy.
- Iodine: adequate daily iodine (approx. 150 µg adult; higher in pregnancy) is needed; excess iodine can trigger autoimmune thyroid disease and iodine‑induced hyperthyroidism.
Practical recommendations (for clinicians and patients)
- For diagnosis: measure TSH + free T4 as primary tests. Add TPO Ab when autoimmune disease suspected, especially in pregnancy/infertility.
- Consider repeating unexpected or discordant results and checking for assay interference or using a different lab when labs contradict the clinical picture.
- When patients remain symptomatic on levothyroxine despite normalized TSH:
- Exclude other causes (menopause, anemia, depression, sleep disorders, metabolic disease).
- Consider checking total/free T3 by mass spec if available.
- Consider a trial of combination therapy (synthetic T4+T3 or DTE) after informed discussion and close monitoring.
- In elderly patients, be cautious about treating mildly elevated TSH (age‑specific reference ranges matter).
- Pregnant women and those planning pregnancy: screen and monitor thyroid function carefully; consider TPO positivity a relevant risk factor.
- Advise against high‑dose iodine supplements unless medically indicated; excessive iodine can trigger autoimmune or hyperthyroid conditions.
- Prefer established, regulated manufacturers; be cautious with unverified compounding pharmacies and unvalidated slow‑release claims.
Notable quotes / memorable insights
- “T3 is the biological reactive hormone. Why would you not measure it?” — Dr. Bianco (emphasizing limitations of ignoring T3).
- “In the tissue, T3 levels can change tenfold in a few hours — you won't see that in the blood.” — highlights the importance of local deiodinase control.
- “Hypothyroidism is not a trivial disease — it’s a risk factor for cardiometabolic disease and associated with increased mortality.” — Dr. Bianco (argues for more attention to residual risk even after TSH normalization).
Actionable next steps / resources
- Patients: if you have persistent symptoms despite normalized TSH on levothyroxine, discuss:
- Re‑evaluation for other causes.
- Possibility of combination therapy trial.
- Whether advanced testing (mass spec T3) or referral to an endocrinologist is appropriate.
- Clinicians: consider measuring free T3 by mass spec when possible in complicated cases; be open to combination therapy for selected patients after informed consent and monitoring.
- Read Dr. Bianco’s book: Rethinking Hypothyroidism — for deeper patient‑ and clinician‑oriented discussion.
- Follow evolving research on slow‑release T3 formulations and standardized mass spec assays.
This summary captures the main physiology, clinical implications, diagnostic caveats, treatment options, and Dr. Bianco’s perspective on where thyroid care should evolve.