Acella NP Thyroid recall: Ethical yet low-risk

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Can a 1.053 mcg excess in LT3 “cause” thyrotoxicosis?

Yes, maybe, or not at all. It depends. [This section was enhanced June 5]

In a person on desiccated thyroid hormone therapy, adding T3 can have several possible responses, depending on the relative levels of T4 and T3 combined.

  • BENEFIT: Underdosed to Euthyroid
  • NO RISK: Euthyroid to Euthyroid (no noticeable change)
  • MILD to MODERATE RISK: Euthyroid to Mildly overdosed
  • MINORITY AT HIGH RISK: Mildly overdosed to more overdosed

If only the T3 level increased in potency to 115% of its stated content, per tablet, thyrotoxicosis is only possible if one is already close to a state of mild overdose or mildly overdosed already, or if has a susceptibility to produce Graves’ disease antibodies, as explained below.

Acella stated in their recall notice that they had received only TWO patients’ reports of adverse effects to date, but they provided contact information for others to report more.

Wide variation in response to DTE thyroid therapy

In the image below, you can see how two variables influence response 1) innate “poor converter” vs “good converter” status, and 2) dosing level.

[NOTE: Grey zone = reference range. Green arrow, T4 activating enzymes D1 and/or D2; Red arrow, D3, the enzyme that deactivates T4 and T3. “Mild overdose” is the poor converter.]

Poor converters need relatively more T4, but they get less T3 out of it than a good converter of T4.

Good converters have a larger T3:T4 ratio and may not need as high a dose.

(The terms “poor converter” and “good converter” come from Midgley et al, 2015).

Newer thyroid science since 2012 teaches us that in general, Free T3 must usually be above mid-reference to be symptom free in LT4 monotherapy (Ito, 2012, 2017, 2019; Larisch et al, 2018; Hoermann et al, 2019). We can learn from their research and apply it to DTE and T3-T4 combination therapy. Compassionate teams of research endocrinologists have finally listened to patients’ symptoms and learned that they do speak clearly: true optimization involves titrating the dose to achieve individualized FT3 levels that can remove symptoms of hypo- and hyperthyroidism.

In contrast to LT4 monotherapy, NP Thyroid and most other DTE preparations yield a FT4 lower in reference than the FT3. Depending on the individual’s metabolic setpoint, FT3 may need to be higher in reference range than it is in LT4 monotherapy, as shown.

Poor converter: Hypo to Euthyroid. This person might be hypothyroid if their thyroid hormone metabolism naturally has a higher setpoint. If a they were given a new batch of NP Thyroid with the same amount of LT4 but a little more LT3, it might be enough to help boost them a little.

Poor converter & Good converter: Remain euthyroid. On the other hand, the good converter and poor converter in the model above may both be euthyroid. If you give them 1.035 mcg more LT3, they may have enough metabolic flexibility to adapt and compensate. They may remain euthyroid.

Poor converter & Good converter : Euthyroid to mild overdose. If either person is near the upper limit of their optimal dose, and/or if they have susceptibility to factors that enhance T4-T3 conversion beyond normal, it might not take much to tip the balance into mild overdose.

Factors that can tip the balance include

  • Strong DIO1 and DIO2 deiodinase genes that support T4-T3 conversion,
  • Graves’ disease antibodies (also present in 10% of Hashimoto’s patients), and
  • T3-hypersecreting thyroid nodules.

In these patients, even a slightly higher T3 dose increase can have a domino effect on overall T3 supply. Day by day, dose by dose, it can build up over several weeks to the point of symptomatic impact on tissues that are vulnerable: muscle weakness, tremors, and periods of rapid heart rate.

Mild overdose to moderate overdose: Even a state of mild overdose will be distressing and uncomfortable for the thyroid patient. At mild levels of overdose, the metabolism will be in a state of conflict between the enzymes that enhance T4-T3 conversion on the one hand, and local deactivation of hormones on the other hand.

  • D1 and D2 enzymes convert T4 to T3 throughout our bodies. If we have some thyroid tissue left, their conversion rate will be enhanced as blood flows through thyroid tissue, and if we have some TSH in blood, it is enhanced further. This is the principle known in thyroid science as the “TSH-T3 shunt” (Hoermann et al, 2015). In addition, when T3 is higher in reference, it upregulates T4-T3 conversion via D1 (Maia et al, 2011).
  • D3 enzyme, our body’s “thyroid fire brigade,” deactivates T4 to Reverse T3 while simultaneously converting T3 to an inactive form of T2. In adults, this enzyme is normally expressed only in brain (central nervous system) and skin, but in a state of thyroid hormone excess, D3 can re-express and can dominate in any tissue, just as it comes to dominate in critical illness (Bianco et al, 2019).

Mild overdose creates a tug of war in the body between organs and tissues that express different ratios of the three thyroid metabolism enzymes D1, D2 and D3. For example,

  • The brain can paradoxically suffer mild hypothyroidism because the inactivation enzyme D3 dominates over D2, especially when T4 levels are higher and progressively deactivate D2. In brain, there is little to no D1 to enhance T4-T3 conversion and fight back against D3’s higher deactivation rate.
  • At the same time, the cardiovascular system can suffer overstimulation. It is not dominated by D3 until a significant cardiovascular injury has occurred. The earliest symptom is that the average resting heart rate begins to rise above normal.

However, our body’s D3 fire brigade can’t stop a building thyroid fire. If a steady supply of T4 and T3 from medication plus residual thyroid function continues to supply more raw material, the supply rate and T4-T3 conversion rate can combine to overwhelm D3 enzyme and create more uniform symptoms of thyrotoxicosis.

Mild and moderate overdose are nothing compared to untreated Graves autoimmune hyperthyroidism, in which levels may be 2-4 times normal.

Nevertheless, if a hypothyroid person has genetic susceptibility to create Graves’ antibodies, a damaged or removed thyroid gland can’t stop T3 from rising in circulation — there is no such thing as an “antibody-ectomy.” Graves’ disease antibodies can act directly on D2 enzymes’ TSH receptors to stimulate the rate of T4-T3 conversion even further than normal, and this happens both in peripheral tissues and in any remaining thyroid tissue.

Therefore, this recall is important to protect the category of metabolically-susceptible hypothyroid patients.

  • The minority of hypothyroid patients on DTE who have the capacity to create Graves’ disease antibodies are the most at risk as their T3 rises closer to the top of reference.
  • Next in line for trouble are any DTE patients who are dosed near the upper limit of their “optimal” hormone levels, especially those whose T4 and T3 are both near the upper part of reference. They must be vigilant.
  • Meanwhile, DTE-underdosed patients, and those who are poor converters but nowhere near excess, are not susceptible at all. They may even experience a welcome boost, or no difference at all.

Other factors that matter

[section added June 5]

Other factors that may influence the impact of 1.035 mcg of extra T3 are the following:

Relative changes in DTE’s T4 potency within the acceptable 90-110% specifications applied to DTE pharmaceuticals and most other drugs (except synthetic levothyroxine).

Synthetic Levothyroxine’s specification for potency was narrowed to 95-105% in the year 2006 for this very reason; persons dosing thyroid hormone can be very susceptible to a 20% variance. The 10% variance protects patients.

Consider that both T4 and T3 are in DTE medication and the T4 content dominates. If the T4 potency per DTE tablet was previously at 108% and then dropped to 92% on average, the T3 “superpotency” could be counterbalanced by a T4 “subpotency” within each pill. On the other hand, if T4 potency went from 92 to 108 alongside a rise in T3 potency, they would together increase the overall superpotency per tablet.

In addition, because of the FDA specification allowing some variance from pill to pill and batch to batch, anyone switching from one synthetic Levothyroxine brand to another, or one LT3 brand to another, or one DTE brand to another, is vulnerable to even larger shifts in supply as one brand may currently be at the lower end of potency and the other at its higher end.

Change in season of year. Hypothyroid patients who depend on medication for their T4 and T3 supply can experience significant T3 and T4 loss in the colder season of the year. Conversely, they can get a bonus in supply in the warmer seasons of the year (Gullo et al, 2017). Those without any thyroid tissue will experience the most extreme seasonal variation because they lack the equipment for metabolic adaptibility (a healthy thyroid regulated naturally every day by TSH circadian rhythms). As winter turns to spring and summer, the risk of thyrotoxicosis rises even at the same dose of thyroid hormone, and those who dose T3 or DTE may need to temporarily cut back.

Pregnancy and post-partum. During early pregnancy, hCG hormone from the placenta can enhance stimulation of remaining thyroid tissue even if TSH is low or suppressed. However, unlike TSH and TSAb antibodies, hCG tends to enhance T4 relatively more than T3. Changes in the immune system post-partum can cause thyroid antibodies to appear or re-express, along with imbalances in thyroid metabolism as the body readjusts. Learn more about influence on maternal outcomes in Part 2 of this series.

Nonthyroidal illness (NTIS), and recovery from NTIS. Significant changes in thyroid hormone metabolism occur during severe illness. It takes more than just a common cold or “stress” to enter severe NTIS, when D3 enzyme overpowers thyroid metabolism and rapidly lowers T3 supply in D3-expressing cells. Even in a person well dosed with thyroid hormone, NTIS after a significant surgery can swiftly deplete T3 to a level below reference, as shown in a study of 6 men dosed on Synthroid (Wadwekar & Kabadi, 2004). During recovery from NTIS (if the patient is capable of recovery), TSH swiftly rises, sometimes above reference into subclinical hypo range, stimulating thyroid tissue to oversecrete T3 and to over-convert T4 to T3, resupplying the T3 deficit. TSH remains high enough until hormone levels rise high enough for health, at which time, negative feedback kicks in and reduces TSH to normal. In this way, TSH cooperates with thyroid tissue to restore healthy thyroid metabolic balance.

Iodine dosing and other substances. Anyone with a thyroid tissue remnant is vulnerable to the power of iodine deficiency and excess and should become aware of its power to distort and limit as well as enhance thyroid hormone synthesis and the entire HPT axis. If you are tempted to experiment with iodine, I urge you to learn more about the science of autoimmune susceptibility to iodine over- and underdose. Read more broadly than the literature written by iodine-dosing advocates; as you google, include the term “ncbi” to focus on scientific articles found in the NCBI PubMed database.

Many other thyroid myths surround “T4-T3 conversion enhancement” by supplements such as selenium. True selenium deficiency hinders the deiodinase enzymes that convert T4 to T3. However, if you are not selenium deficient, you cannot over-enhance T4-T3 conversion rate by dosing selenium further. The D3 enzyme is also a selenoprotein, so while alternative medicine practitioners often claim you are “enhancing” conversion rate, you are also enhancing your body’s ability to convert T4 to RT3 and T3 to an inactive T2 at whatever rate your metabolism sees fit. Selenium dosing is still very helpful for many autoimmune thyroid patients, but for other purposes science reveals, such as enhancing the natural antioxidant glutathione and reducing TPO antibodies. Be cautious: Selenium has a toxicity level, and so do many other vitamins and minerals.

Thyroid hormone economy is highly complex, and many other substances and medications are known to enhance or hinder T4 and T3 supply and ratio. “More is not always better” when it comes to supplements. Various pathways can be manipulated by excess and deficiencies:

  • Remaining thyroid tissue’s synthesis of T4 and T3 (i.e. iodine, goitrogens, fluoride, iron)
  • TSH secretion in the pituitary (i.e. leptin from fasting vs obesity; dopamine; cortisol)
  • T4-T3 conversion rate (i.e. kaempferol; inflammatory cytokines)
  • Post-receptor T3 signalling (i.e. vitamin A metabolites such as retinol; beta-blockers; cortisol)

In summary: Let’s all be vigilant. Always.

Pharmaceutical quality control is paramount in thyroid medication, and that’s why it’s so important and so ethical for Acella to announce this recall.

DTE pharmaceticals are more complex because they contain 2 hormones, but Levothyroxine pharma is extremely vulnerable to impurities due to poor stability.

Too many metabolic factors are involved for a person to say that “hyperthyroidism” (or more accurately, “thyrotoxicosis”) is the only direction of risk when “superpotency” of T3 alone rises.

It truly depends. Some patients will get a welcome boost from an extra 1.035 mcg of T3; others will notice nothing; others will go hyper. One cannot predict the patient’s response without knowing a person’s FT3 and FT4 levels and thyroid metabolism strengths and handicaps. The body’s control over T4 and T3 levels and ratios is severely compromised by both thyroid disease AND thyroid therapy, and TSH is not in control anymore.

Pharmaceuticals are only one player in the struggle to achieve and maintain optimal thyroid hormone balance. The patient and the doctor must be equally vigilant. Thyroid patients who are susceptible to overdose or over-conversion (or underdose and poor conversion) must be protected from any and all factors that can push them over the edge into illness.

Jet metaphor: In thyroid therapy, it’s like we’re manually flying a complex jet with limited-capacity fuel tanks and a partial or complete TSH auto-pilot failure or disconnect. Normally the body’s thyroid-jet can synthesize its own fuel supply and handle all turbulence, but we can’t. We have to continually refuel mid-flight with raw T4, and some of us also need pre-refined T3, which our healthy thyroid would have secreted at a flexible rate.

If you are “stable” on thyroid therapy, you are lucky, because it’s truly not that easy for everyone. Some doctors think it’s easy, but they don’t see everything we go through, and a normalized TSH covers all therapy sins.

Continue to Part 2

Acella NP Thyroid recall: maternal risk inflated

  • Thyrotoxicosis in pregnancy
  • Hypothyroidism and underdose: Significant risks
  • Risk of testing only TSH and not FT4 in pregnancy
  • Acella’s recall notice: Consider clarity, focus
  • Conclusion: What we can do
  • References

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