[@PeterAttiaMD] 373 – Thyroid function & hypothyroidism: how new approaches are transforming care

Link: https://youtu.be/jT33TbUVCGI

Short Summary

This podcast episode of the Drive Podcast features Peter Aia interviewing Dr. Tony Bianco, a thyroid researcher and medical school dean, about the intricacies of thyroid hormone regulation, hypothyroidism, and hyperthyroidism. They discuss thyroid physiology, T4/T3 conversion, diagnostic challenges, controversies surrounding treatment strategies (T4 monotherapy vs. desiccated thyroid or combination therapy), and the need for improved measurement techniques and slow-release T3 formulations to address the significant impact of thyroid disorders on patients' lives.

Key Quotes

Here are five quotes from the transcript that highlight valuable insights:

1. "So, what's happening is that the hypothalamus...is detecting that you're not eating...Thyroid hormone accelerates energy expenditure...So the hypothalamus says, well I have to reduce, to take my foot off the gas here so that even though there's less food coming in...we're going to reduce the rate at which I'm burning the fuel here." - This describes the body's adaptive response to fasting, where the hypothalamus reduces thyroid hormone activity to conserve energy.

2. "And so is that ratio which some people have talked about the ratio of reverse pardon me of free T3 to reverse T3 that rising level of that ratio is that a poor man's proxy of aggregate thyroid activity in the body or is that just too coarse a manner to look at it?... No, I think the ratio is useful is a good surrogate of diagonese activity- because honestly we can't measure the diagonases in humans, right?" - This highlights the clinical utility of the T3/rT3 ratio as a surrogate marker for diodinase activity, given the difficulty of directly measuring diodinases in humans.

3. "TSH doesn't do anything. None of the symptoms of hypothyroidis can be attributed to changes in TSH. has to work through the thyroid gland. So the TSH stimulates the thyroid to grow to function to secrete thyroid hormones." - This clarifies the role of TSH, emphasizing that it is not directly responsible for hypothyroid symptoms, but rather acts as a regulator of thyroid hormone production.

4. "You know what? Mortality is 2.5 greater in the patients taking levothyroxine with hypothyroidism. We just....we know that retrospectively...and they die of cardioabolic diseases. They have increased cholesterol. Uh so the number one co-medication that is prescribed with lipothy is statin." - This presents a surprising and concerning statistic about mortality rates in levothyroxine-treated hypothyroid patients, suggesting that the medication may not fully address all the underlying metabolic issues. It also suggests increased cholesterol.

5. "We don't have a single clinical trial demonstrating the efficacy of levothyroxine...for example, if you let's look at hard uh outcomes. Let's look at mortality. Take patients uh control population and compare with the population with hypothyroidis treated with levothyroxine. Let's look at mortality. We never looked at that." - This discusses the lack of clinical trials using levothyroxine in practice.

Detailed Summary

Here's a detailed summary of the YouTube video transcript, organized into bullet points:

I. Introduction

• The Drive Podcast, hosted by Peter Aia, features Dr. Tony Bianco, Dean of the Medical School in Galveston, TX, and a thyroid research expert.
• The podcast aims to demystify thyroid hormone replacement and diagnosis, which are considered more complex than other endocrine systems like testosterone.

II. Dr. Bianco's Research Focus

• Dr. Bianco's research focuses on understanding what thyroid hormone (specifically T3) does at the tissue and cellular levels.
• He investigates how thyroid hormone affects chromatin folding, thereby regulating gene expression.
• This gene regulation changes cell behavior and has consequences for the entire tissue, organ, and body.
• The goal is to better serve patients with hypothyroidism by understanding how thyroid hormone works in different tissues.

III. Common Knowledge and Hypothyroidism

• Most people know the thyroid gland sits over the voice box and produces a hormone.
• The hormone produced is T4 (inactive), which is converted to T3 (active) in the body.
• Thyroid hormone is known to regulate energy expenditure, body temperature, mood, and sleep.
• Hypothyroidism is a condition where the body doesn't produce enough thyroid hormone.
• Many people with hypothyroidism supplement with thyroid hormone replacement.

IV. Basic Thyroid Physiology

• Iodine: The thyroid gland takes up iodine from the blood to produce hormones. Iodine is crucial for thyroid function, sourced from diet (seafood) and iodized salt.
• Hormone Storage & Release: The thyroid stores large amounts of T4 and slowly releases it into circulation daily.
• T4 vs. T3:
  • T4 is largely inactive.
  • T3 is the active form and is created by removing one iodine atom from T4.
  • Cells have receptors that bind T3 with high affinity but have low affinity for T4.
• Evolutionary Perspective: The T4/T3 system evolved to preserve iodine, which was historically deficient.
• Hormone Half-Lives:
  • T4 has a long half-life (approximately 8 days).
  • T3 has a short half-life (approximately 12 hours). This allows for tight regulation of thyroid hormone action. Once activated, T3 triggers its own destruction.
• Diodinases: These are enzymes that remove iodine atoms from T4 to create either T3 or reverse T3.

V. Reverse T3 (rT3)

• Reverse T3 is an alternative form of T3 created by removing an iodine atom from the inner ring of T4, while T3 involves removing from the outer ring.
• Reverse T3 is largely inactive (essentially dead).
• Diodinases convert T4 to either T3 (active) or reverse T3 (inactive), offering an alternative pathway to regulate thyroid hormone.
• The body can preferentially convert T4 to rT3 to reduce thyroid hormone activation.

VI. Fasting and Thyroid Hormone Changes (Example)

• Peter Aia shares his experience of fasting and its effects on thyroid hormones:
  • Before Fast: TSH = 2, Free T3 = 0.3, Reverse T3 = 10
  • After Fast: TSH = 7, Free T3 = 0.2, Reverse T3 = 35
• Explanation:
  • The hypothalamus detects low food intake (low insulin and leptin).
  • The hypothalamus reduces TSH to decrease energy expenditure. TSH is "inappropriately normal".
  • The thyroid secretes less T4 and T3.
  • T4 is preferentially converted to reverse T3.
  • Reduced insulin and carbohydrate intake reduces D1 activity in the liver, slowing rT3 clearance.
• The T3 to reverse T3 ratio is considered a surrogate marker for overall diodinase activity. A falling ratio suggests metabolic slowdown.

VII. Diodinase Types (D1, D2, D3)

• D1: Found in the liver and kidneys. It's not a very efficient enzyme but is important in clearing reverse T3 from the circulation. D1 activity is sensitive to insulin and carbohydrates.
• D2: Superb enzyme with 1,000x more affinity for T4 than D1. Responsible for making about 80% of the T3 produced outside the thyroid gland.
• D3: Solely inactivates thyroid hormone. Takes T3 and transforms it into T2 (a dead molecule) and converts T4 to rT3.

VIII. Diiodinase Locations and Functions

• D2 primarily converts T4 to T3, activating thyroid hormone.
• D3 mostly inactivates thyroid hormone, leading to T2 or reverse T3.
• Iodine from reverse T3 is recycled.

IX. Hypothalamus and TSH Regulation

• The hypothalamus produces TRH (TSH-releasing hormone).
• TRH stimulates the pituitary gland to produce TSH (thyroid-stimulating hormone).
• TSH stimulates the thyroid gland to grow, function, and secrete thyroid hormones.
• Symptoms of thyroid dysfunction are due to thyroid hormone imbalances (not directly due to TSH levels).
• Central hypothyroidism is when the pituitary gland doesn't produce enough TSH.
• Peripheral levels of T4 and T3 are consistent throughout the day, unlike insulin or cortisol.

X. Four Major Hormone Systems

• The discussion mentions four main hormone systems:
  1. Sex hormone system
  2. Thyroid system
  3. Adrenal system
  4. Fuel partitioning (insulin/glucagon) system
• The thyroid system is generally the most consistent of the four, except in extreme situations.

XI. Tissue-Specific Thyroid Hormone Regulation

• Diiodinases allow for tissue-specific regulation of T3 levels, even when blood levels are stable.
• Example: Cold exposure significantly increases T3 levels in brown fat (for heat production) without changing blood T3 levels.
• Most T3 in the brain is produced locally through the type 2 diiodinase.
• The medial basal hypothalamus is outside the blood-brain barrier, allowing it to sense both peripheral hormone levels and locally produced T3.
• The hypothalamus and pituitary have a lot of D2, allowing them to sense both T3 and T4. T4 must be locally converted to T3.

XII. T3 Measurements and Challenges

• Dr. Bianco emphasizes the importance of measuring T3, even though some schools of thought discourage it.
• There is an incomplete understanding of thyroid physiology among many practitioners.

XIII. T3, T4, Free T3, and Free T4

• Most T3 and T4 in the circulation (99.5%) is bound to proteins (like thyroxine-binding globulin - TBG).
• Only the free (unbound) hormone is biologically active.
• Free T3 and free T4 are better diagnostic markers because they reflect what's available to tissues. Total hormone levels can be affected by changes in binding proteins (e.g., estrogen during pregnancy).
• Free T4 has a gold standard assay, but free T3 does not. T3 assays are not good and have high variability.
• Dr. Bianco advocates for mass spectrometry (mass spec) for accurate T3 measurement, but notes that clea-approved mass spec assays aren't readily available. Reverse T3 assays are also inaccurate.
• Laboratories need to use the same assay type for consistent monitoring, even if it's not perfectly accurate.

XIV. Genetics and Thyroid Hormone

• Some genetic influence exists on thyroid hormone levels, but its clinical relevance is debated.

XV. Male/Female Differences

• TSH ranges tend to be broader in women than in men. Men have tighter thyroid regulation.

XVI. Prevalence of Thyroid Disorders

• Hypothyroidism (underactive thyroid) is far more common than hyperthyroidism (overactive thyroid).
• Approximately 4-5% of the adult population has hypothyroidism (around 20 million people in the US).

XVII. Hyperthyroidism

• Common Causes:
  • Graves' Disease: An autoimmune condition where antibodies stimulate the thyroid gland.
  • Hyperfunctioning Nodules: Growths in the thyroid that autonomously produce excess hormone.
• Symptoms: Heart palpitations, weakness, jitteriness, difficulty sleeping, rapid reflexes, and weight loss.
• Diagnosis: Low TSH, elevated free T4 and/or T3. Test for antibodies (Graves').
• Treatment (Graves' Disease):
  • Medications: Anti-thyroid drugs that inhibit hormone production.
  • Surgery: Partial or complete thyroidectomy.
  • Radioactive Iodine: Destroys the thyroid gland.
• Radioactive iodine is no longer considered safe due to increased cancer risk.

XVIII. Hypothyroidism

• Detection: Often detected through routine screening rather than symptom-driven diagnosis.
• Most Common Cause: Hashimoto's disease (autoimmune thyroiditis), where the body attacks and destroys the thyroid. The size of the thyroid gland reduces.
• Typical Treatment: Hormone replacement therapy with synthetic thyroid hormone (levothyroxine/T4). The body destroys the thyroid as well.
• Pregnancy and TPO: Positive TPO antibodies during pregnancy increase the risk of miscarriage and prematurity, even with normal thyroid function. May indicate something else is being attacked.
• Other Autoimmune Links: Positive TPO antibodies may be associated with antibodies against brain tissue.
• Prednisolone: Has been used to reduce TPO levels in an attempt to aid fertility.

XIX. Hashimoto's Disease

• The standard of care is to replace the hormone lost by the autoimmune system attacking the thyroid gland, rather than directly address the autoimmunity.
• Positive TPO, normal thyroid tests means the body is probably in the honeymoon phase. Should check every 3 months.

XX. Typical Biomarkers for Hashimoto's

• Elevated TSH
• Reduced free T4
• Positive TPO antibodies (though not always present)

XXI. Non-Hashimoto's Hypothyroidism

• Can be caused by surgical removal of the thyroid, radioactive iodine, congenital hypothyroidism.

XXII. Clinical Trials and Steroids

• No clinical trials are examining steroid use to eradicate Hashimoto's.

XXIII. Thyroid Replacement Strategies

• FDA-Approved Therapies:
  • T4 monotherapy (levothyroxine) - multiple brands
  • T3 monotherapy (liothyronine)
• T4 monotherapy is considered the standard of care. T3 alone is rare.
• Reasons for Favoring T4 Monotherapy: Easy to take, long half-life, allows the body to do its job of converting to T3.
• Challenges with T3 Monotherapy: Short half-life, can cause surges of energy followed by crashes.

XXIV. Desiccated Thyroid Extract

• A powder made from pig thyroid glands, containing both T4 and T3.
• Exists because it predates the FDA. It does not have a current FDA indication.
• The product has been grandfathered in, but is still under the FDA's control and there are recalls.
• Argument AGAINST Desiccated Thyroid Extract:
  • Provides a bolus of T3 (not gradual release), potentially causing dangerous spikes.
  • Historical concerns about inconsistent potency between different manufacturers. No evidence to support the spikes.
• Arguments FOR Desiccated Thyroid Extract:
  • Replaces both T4 and T3, mimicking the natural thyroid gland output.
  • Potency can now be standardized with mass spec methods.
  • Studies show it's as safe as levothyroxine and that patients prefer combination therapy.

XXV. Efficacy of Levothyroxine

• Levothyroxine normalizes TSH, but doesn't always normalize T3 levels in all tissues.
• There is NO clinical trial demonstrating the efficacy of levothyroxine.
• Retrospective studies suggest higher mortality rates in patients taking levothyroxine. Those patients have increased cardiobolic diseases and cholesterol.

XXVI. Mortality and Levothyroxine

• Elevated mortality rates with levothyroxine could be due to:
  • Underlying comorbidities associated with hypothyroidism.
  • Incomplete restoration of euthyroidism (particularly in the liver, leading to persistent high cholesterol).
• LDL cholesterol is cleared by the liver which may not occur effectively during hypothyroidism.
• The liver may remain hypothyroid even with normal peripheral numbers.
• The commonly co-prescribed medication, statins, are there because the metabolism has not returned to normal.
• One study showed a 30% mortality reduction with combination therapy (T4 + T3) compared to levothyroxine alone. However, this comes with the bias of health-conscious patients seeking dual therapy with health-conscious doctors. 50% were on dessicated and 50% were on T3/T4.
• Before the hypothyroidism diagnosis, however, the admission rates for the combination group were similar. The researchers did control for co-morbidities, BMI, sex, and age.

XXVII. "Functional Medicine" and Over-Diagnosis

• Discussion of the concept, as applied in some functional medicine settings, that "everyone has hypothyroidism."
• While hypothyroidism shouldn't be missed, there can also be an overdiagnosis of it.
• Symptoms of hypothyroidism (fatigue, weight gain, hair loss, etc.) are non-specific and can be caused by other conditions (anemia, menopause, etc.).
• Basal body temperature is not a reliable indicator because low body temp does not mean low thyroid function.
• Blinded analyses of symptom treatment are insufficient to diagnose.

XXVIII. Secondary Hypothyroidism

• Occurs when the pituitary gland or hypothalamus fails to produce enough TSH.
• Requires a LOW free T4 and a normal or low TSH.
• In such cases, imaging of the pituitary/hypothalamus is warranted.

XXIX. Compounded Control-Release T3

• There is NO scientific evidence to support the effectiveness of controlled-release compounded T3. Not a single published paper shows a slow-release profile with compounded products.
• Pharmacies may struggle with accurate T3 dosing due to the small amounts involved.
• Dr. Bianco does not recommend compounded formulations due to lack of standardization.

XXX. Preferred Hypothyroidism Treatment

• Start with T4 (levothyroxine) as a first-line treatment.
• Treat hypothyroidism as a risk factor for other diseases and do more intense care and follow-up.
• For patients not feeling well on levothyroxine, eliminate other potential causes (co-morbidities, menopause, etc.) before adding combination therapy.
• Synthetic combination is equally as good as desiccated.
• The best ratio, however, as tested by Dr. Celenko in 1965, is 3.5 or 4 to 1. This is incidentally the ratio in desiccated thyroid.

XXXI. Choosing Desiccated Products

• Consult the FDA website for recalls on thyroid hormone products.

XXXII. Branded vs. Generic Levothyroxine

• Studies suggest there is no difference between branded and generic levothyroxine.
• Pharmacies are often able to switch.

XXXIII. Goal of Therapy

• Traditional approach: Normalize TSH.
• Dr. Bianco: Normalize TSH and improve patient symptoms and free T4. If not, continue to add a more specialized compound for those who cannot resolve on TSH/FT4 alone.
• Justifying not doing a TSH normalized treatment: Patients with depression. No antidepressants work for all, and biochemical uyroidism does not mean clinical uyroidism.

XXXIV. Unusual Clinical Case Scenarios

• High TSH, Treated, Better After Discontinuation: Interference in TSH assays. Also, can be explained with rodent protein antibodies.
• Inconsistent Response to Thyroxine: Can't bring TSH back to normal. Treat the symptoms more than the numbers.
• Over Suppression with Low T4, Good FT3 levels, and No Improvement in Symptoms: Use your clinical judgment and make sure that the free T4 remains in the normal range.

XXXV. Iodine Supplementation Risks

• Excessive iodine intake can increase the risk of autoimmune thyroid disease.
• In Japan, their normal diets are higher on the iodine, which causes increased autoimmune issues.
• Iodine excess can cause autoimune hypo, or hyperthyroid with a nodule.

XXXVI. Male/Female Differences in Hypothyroidism

• Hypothyroidism is much more prevalent in women (10:1 ratio).
• Possible explanations: Female thyroids may leak more antigens due to the impact of sexual hormones. There is no real explanation for why that is.

XXXVII. Subclinical Hypothyroidism

• High TSH, normal FT4, normal FT3 and antibodies, no symptoms. Then repeat testing and treat those who will develop hypothyroidism through clinical testing.

XXXVIII. Treatment with Medication

• Start at a TSH of 8 to 9, the patient feels symptomatic, then discontinue medication. Just keep an eye on the FT4.

XXXIX. Treatment Protocol at 80

• It is okay to have a TSH of 8. Then do not treat unless abnormal.

XL. Call to Action

• There needs to be better treatments as patients suffer a lot.
• It needs to move from the TSH to T3 measurements.
• Low release T3 should be available in FDA forms.

XLI. Books

• Rethinking Hypothyroidism by Tony Bianco. There are warring factions on both sides.