#373 – Thyroid function and hypothyroidism: why current diagnosis and treatment fall short for many, and how new approaches are transforming care | Antonio Bianco, M.D., Ph.D.
Dr. Antonio Bianco, a physician-scientist and expert in thyroid physiology, discusses the complex biology of thyroid hormones, the limitations of TSH-only diagnosis, and the controversies surrounding hypothyroidism treatment. He explores the roles of deiodinase enzymes, genetic variability, and the potential benefits of combination therapy over T4 monotherapy.
Deep Dive Analysis
18 Topic Outline
Introduction to Dr. Antonio Bianco and Thyroid Research Focus
Fundamental Biology of Thyroid Hormone Production and Action
Role of Deiodinases and Reverse T3 in Thyroid Hormone Regulation
Impact of Fasting on Thyroid Hormone Levels and Metabolism
Hypothalamus-Pituitary-Thyroid Axis and TSH Regulation
Importance of Understanding Thyroid Physiology for Treatment
Thyroid Hormone Testing: Free vs. Total Levels and Assay Limitations
Genetic and Sex-Based Variability in Thyroid Regulation
Hyperthyroidism: Causes, Symptoms, Diagnosis, and Treatment Options
Hypothyroidism: Autoimmune Causes and Diagnostic Biomarkers
Thyroid Hormone Replacement Therapy: T4 Monotherapy vs. Combination
Desiccated Thyroid Extract: History, Pros, and Cons
Mortality and Comorbidities in Hypothyroidism Treatment
Debunking Misconceptions in Hypothyroidism Diagnosis
Challenges with Compounded Controlled-Release T3
Risks of High-Dose Iodine Supplementation
Managing Subclinical Hypothyroidism and Age-Related TSH Changes
Future Directions in Thyroid Diagnosis and Treatment
7 Key Concepts
T4 (Thyroxine)
T4 is the primary pro-hormone secreted by the thyroid gland, containing four iodine atoms. It is largely inactive and serves as a circulating storage form with a long half-life of about eight days.
T3 (Triiodothyronine)
T3 is the active form of thyroid hormone, produced by removing one iodine atom from T4. T3 binds to cellular receptors with high affinity, regulating gene expression and metabolism, but has a short half-life of about 12 hours.
Deiodinases (D1, D2, D3)
These are enzymes that regulate thyroid hormone activity at the tissue level by either activating T4 into T3 (D1, D2) or inactivating T4 into reverse T3 (D1, D3) and T3 into T2 (D3). D2 is particularly efficient, producing about 80% of T3 made outside the thyroid gland, especially in the brain and hypothalamus.
Reverse T3 (rT3)
Reverse T3 is an inactive form of T3 produced when an iodine atom is removed from the inner ring of T4. Its production increases when the body aims to reduce thyroid hormone action and conserve energy, such as during fasting.
Hypothalamus-Pituitary-Thyroid (HPT) Axis
This is a regulatory system where the hypothalamus releases TRH, stimulating the pituitary to release TSH, which then stimulates the thyroid gland to produce T4 and T3. This axis maintains stable thyroid hormone levels in the blood, but local tissue T3 levels can vary significantly due to deiodinase activity.
Hashimoto's Disease
The most common autoimmune cause of hypothyroidism, where the body's immune system produces antibodies (e.g., TPO antibody) that attack and destroy the thyroid gland. This leads to reduced thyroid hormone production and is typically treated with hormone replacement.
Subclinical Hypothyroidism
This condition is characterized by an elevated TSH level (e.g., 5-10 mIU/L) but normal free T4 levels. Patients may or may not experience symptoms, and the decision to treat depends on factors like age, symptoms, and antibody status.
10 Questions Answered
The thyroid gland traps iodine from the blood to produce thyroid hormones, primarily the inactive pro-hormone T4, which it stores and slowly releases into circulation.
T4 is activated into the biologically active hormone T3 by deiodinase enzymes (D1 and D2) that remove one iodine atom, primarily in peripheral tissues like the liver, heart, and brain.
Reverse T3 (rT3) is an inactive form of T3 produced by deiodinase enzymes (D1 and D3) when an iodine atom is removed from the inner ring of T4, serving as a mechanism to reduce thyroid hormone action and conserve energy, such as during fasting.
Most T3 and T4 in circulation are bound to proteins and inactive; only the tiny "free" fraction can enter tissues and exert biological effects. Free hormone levels are more accurate for diagnosis as they are not affected by changes in binding proteins.
The existing immunoassay methods for T3 and reverse T3 are not gold standards and have high variability, especially at lower levels, making them less accurate than mass spectrometry, which is not routinely available.
The two major causes are Graves' disease (an autoimmune condition where antibodies stimulate the thyroid) and hyperfunctioning nodules (adenomas) that autonomously produce excess thyroid hormone.
The most common cause is Hashimoto's disease, an autoimmune condition where the body's immune system attacks and destroys the thyroid gland.
While TSH normalization is the primary goal of conventional therapy, many patients on T4 monotherapy still experience symptoms and have increased mortality from cardiometabolic diseases, suggesting incomplete restoration of euthyroidism at the tissue level.
Excessive iodine intake can trigger autoimmune thyroid disease by increasing the antigenicity of the thyroid, potentially leading to hypothyroidism, and can also induce hyperthyroidism in individuals with existing thyroid nodules.
After age 50, the upper limit of the normal TSH range increases by approximately one point every 10 years, meaning an elevated TSH in an older individual (e.g., TSH of 8 in an 80-year-old) may be considered normal and not require treatment.
27 Actionable Insights
1. Request Mass Spec for T3/rT3
When measuring T3 and reverse T3, request a mass spectrometry (LC-MS) assay instead of immunoassay, especially for low levels, due to its superior accuracy and reliability.
2. Measure Biologically Active T3
Advocate for measuring T3 (the biologically active thyroid hormone) when assessing thyroid function, as its omission reflects an incomplete understanding of thyroid physiology.
3. Rely on Labs, Not Just Symptoms
When evaluating for hypothyroidism, rely primarily on TSH and Free T4 lab results rather than symptoms alone, as many symptoms are non-specific and can be caused by other conditions.
4. Monitor Cardiometabolic Health
If you have hypothyroidism, even when treated, consider it a risk factor for cardiometabolic disease and ensure regular monitoring of cholesterol, LDL, and signs of early cardiovascular disease.
5. Re-evaluate Therapy if Symptoms Persist
If you continue to experience symptoms despite normalized TSH and Free T4, discuss with your doctor that the current therapy may not be ideal and explore further options.
6. Advocate for Better Hypo Treatment
Advocate for improved hypothyroidism treatment, including the development of reliable mass spec T3 assays and pharmaceutical slow-release T3 formulations, to address patient suffering beyond just normalizing TSH.
7. Start Hypo Treatment with T4
For initial hypothyroidism treatment, start with T4 monotherapy (levothyroxine), assuming deiodinases are functioning optimally to convert T4 to active T3.
8. Address Comorbidities First
If T4 monotherapy is ineffective, first rule out and address other comorbidities (e.g., menopause, anemia) causing similar symptoms before considering combination T4/T3 therapy for hypothyroidism.
9. Consider Synthetic T4/T3 Combo
If T4 monotherapy is insufficient, consider synthetic T4/T3 combination therapy, which allows for adjusting the T4 to T3 ratio (ideally around 3.5-4:1) to optimize treatment.
10. Adjust TSH Range with Age
Recognize that the normal TSH range increases with age; for individuals over 50, an elevated TSH (e.g., 6 at 70, 8 at 80) may be considered normal and not require treatment.
11. Screen Pregnant Women for TPO
Pregnant women should be screened for TPO antibodies in the first trimester, and if positive, should be referred to a high-risk obstetrician due to increased risk of miscarriage and prematurity, even without overt hypothyroidism.
12. Avoid High-Dose Iodine
Avoid supplementing with excessive amounts of iodine (above 150-250 micrograms daily), as high doses can trigger autoimmune thyroid disease and hyperthyroidism in some cases.
13. Selenium/Vitamin D for Hashimoto’s
If you have Hashimoto’s disease, consider supplementing with selenium, vitamin D, or other antioxidants to potentially reduce TPO levels and prolong the thyroid’s natural function.
14. Monitor TSH with Family History
If you have a family history of hypothyroidism, a rising TSH, and positive TPO antibodies, monitor TSH every three months to make an early treatment decision, even if minimally symptomatic.
15. Diagnose Secondary Hypo by Low Free T4
If you suspect secondary hypothyroidism (normal TSH with symptoms), ensure your Free T4 is below normal; if so, pursue imaging of the pituitary or hypothalamus to rule out underlying issues.
16. Check FDA for Drug Recalls
Regularly check the FDA website for recalls on thyroid medications, including desiccated thyroid extract and levothyroxine, to ensure the safety and potency of your treatment.
17. Choose High-Volume Surgeons
When considering surgery, especially for specialized procedures like thyroidectomies, seek surgeons who perform a high volume of cases (e.g., at least 100 per year) to ensure expertise.
18. Discuss Post-Iodine Cancer Screening
If you’ve had Graves’ disease and received radioactive iodine treatment, consult your doctor about potential increased cancer risk and discuss appropriate additional cancer screenings.
19. Track Personal Baseline TSH
Keep records of your baseline TSH levels from when you were healthy, as this can serve as a personalized target if you develop hypothyroidism.
20. Ensure Daily Iodine Intake
Consume a reasonable amount of iodine daily through diet (e.g., seafood) or supplemented kitchen salt to support thyroid function.
21. Generic Levothyroxine is Comparable
Do not assume branded levothyroxine (Synthroid) is superior to generic versions; studies show comparable efficacy, and pharmacists may switch to generics without notification.
22. Normalize TSH, Free T4
The primary goal of thyroid hormone replacement therapy is to normalize TSH and Free T4 levels, aiming for biochemical euthyroidism, even if some symptoms persist.
23. Monitor for Co-Occurring Autoimmunity
If diagnosed with one autoimmune disease, be aware of the increased risk of developing other autoimmune conditions and discuss this with your doctor for comprehensive monitoring.
24. T3 Not for Hypo Diagnosis
Do not rely on T3 levels for diagnosing hypothyroidism, as the body prioritizes maintaining normal T3 even in early stages; focus on TSH and Free T4 instead.
25. Trust TSH, Free T4 Assays
Trust TSH and Free T4 immunoassay results, especially when consistently using the same lab, but be cautious with T3 and reverse T3 immunoassay results, particularly at low levels.
26. Master Physiology for Treatment
Deeply understand the underlying physiology of a condition to discern genuine therapies from potentially harmful or ineffective treatments.
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6 Key Quotes
From an evolutionary point of view, the evolutionary pressure is iodine deficiency. So the whole system evolved in a way to preserve iodine.
Antonio Bianco
TSH doesn't do anything. None of the symptoms of hypothyroidism can be attributed to changes in TSH. It has to work through the thyroid gland.
Antonio Bianco
Most T3 in the brain does not come from the blood. It comes from being produced locally through the type 2 deiodinases.
Antonio Bianco
Mortality is 2.5 greater in the patients taking levothyroxine with hypothyroidism.
Antonio Bianco
All symptoms of hypothyroidism are not pathognomonic, meaning they're not specific for hypothyroidism. They can be caused by anything, by other diseases, by comorbidities.
Antonio Bianco
After 50 years of age, your TSH will increase by one point. Your upper limit of normal will increase by one point every 10 years.
Antonio Bianco