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Although January is National Thyroid Month, our Clinical Services team gets a lot of queries throughout the year on managing thyroid patients, including those with autoimmune conditions such as Graves’ disease (GD) and Hashimoto's thyroiditis (HT). While thyroid clinical management may seem complicated, understanding some basics of thyroid physiology and the pathophysiology of these autoimmune diseases may help make a difference in patients’ lives.
by Nat Jones, RPh, FAPC, PCCA Clinical Compounding Pharmacist
The thyroid gland produces hormones that serve as the master in energy production and affects almost everything we do. When dysfunctional thyroid performance occurs, the impact can be devastating. Many patients on thyroid replacement therapy (TRT) are still not happy with how they feel.
The thyroid gland produces three main hormones: triiodothyronine (T3), thyroxine (T4) and calcitonin. Monitoring levels of T4 and T3 occur in the hypothalamus and pituitary gland. Thyrotropin-releasing hormone (TRH) produced by the hypothalamus stimulates the pituitary gland to secrete the thyroid-stimulating hormone (TSH), which stimulates both production and secretion of T4 and T3. T4 and T3 then travel in the blood to every cell in the body, including the hypothalamus and pituitary as feedback for production. A TSH test reflects the brain’s assessment of both T4 and T3 levels. A high TSH level usually indicates low levels of the hormones — or hypothyroidism — and a low TSH usually indicates high hormone levels — or hyperthyroidism.
Synthesis of thyroid hormones occurs in the thyroid gland from the substrate of the amino acid tyrosine and iodine. Thyroglobulin (TG) is a large glycoprotein used as the matrix for thyroid hormone synthesis. Ingested iodide is trapped in the thyroid, oxidized and bound to tyrosine to form iodothyronines in thyroglobulin; coupling of iodotyrosyl residues forms T4 and T3. The process requires the presence of iodide, a peroxidase (TPO), a supply of hydrogen peroxide (H2O2), and an iodine acceptor protein (Tg).1
T4 is the major producer and considered a prohormone to T3, the most active form. T4 is converted via the 5’-deiodinase enzymes into T3 and is also converted via the 5-deiodinase into reverse T3 (rT3), an inactive competitor. The role of rT3 is to act as a metabolic governor to help slow energy production — stress increases rT3 production. T3 works at the inner membrane of the mitochondria to stimulate oxidative phosphorylation.
Inadequate T3 presence in the mitochondria results in hypothyroidism, where ATP production suffers and body temperature decreases. If a patient cannot convert T4 to T3 adequately, then supplementation should ideally include both hormones — not just T4. Low selenium can also decrease the conversion of T4 to T3 via the 5’-deiodinase enzyme. In addition, low ferritin (the intracellular storage form of iron) can decrease T4 to T3 conversion. Decades of menstruation and subsequent iron loss is likely one of the functional reasons why more females than males have low conversion.
The basic principle of the (unidirectional) reductive sequential monodeiodinations of iodothyronines. T4 secreted by the thyroid gland can be deiodinated at the 5’-position of its phenolic ring by DIO1 and DIO2 yielding the main thyromimetic hormone T3. Enzymatic removal of the iodine substituent in 5’-position of the tyrosyl-ring of T4 by either DIO3 or DIO1 produces reverse-T3 (rT3), which is devoid of thyromimetic activity but circulates in the blood.2
In HT, antibodies produced against TPO (TPO Ab) attack normal thyroid tissue. Initially, there can be a hyperthyroid release of hormone from the gland; over time the production falls and usually becomes fixed hypothyroidism, requiring thyroid hormone supplementation. It is important to note that you cannot “top off the tank” with a portion of T4 and/or T3 needed — negative feedback will ultimately decrease production, so full supplementation should be the goal from the beginning of therapy. HT is 4.4 times more likely to occur in women than men and affects 1 to 2 percent of people in the United States.3
GD, which represents 60-80% of all cases of hyperthyroidism, is caused by the production of immunoglobulin G (IgG) autoantibodies and thyroid-stimulating immunoglobulin (TSI) — also known as thyroid-stimulating antibody (TSAb).4 These antibodies bind to and activate the receptor, causing the autonomous production of thyroid hormones — hyperthyroidism — as well as thyroid growth. Thyroid growth can cause a diffuse goiter, possibly exophthalmia and bone loss. The standard treatment for GD is antithyroid drugs such as methimazole or propylthiouracil. Many GD patients require surgery or radio ablation to remove the gland, after which thyroid replacement therapy (TRT) is needed. GD is more common in women than men, with onset occurring between ages 20 to 50 years.
There is debate about replacing T4 alone or combinations of T4 and T3 in any ratio, and whether it is best to formulate T4 and T3 in a slow-release capsule using methocel E4M. The half-life of T4 is very long, about 7 days, so a slow-release formulation is not needed. Several T4 commercial options are currently available, and many pharmacists focus on compounding and titrating T3 to accompany commercial T4 products.
Food and beverage interfere with TRT absorption.5 Compounding a slow-release capsule size #1 or larger, which dissolves between 8 to 10 hours, presents multiple occasions for consumption of food and beverage that lead to erratic absorption. Many patients with inflamed GI tracts may have poor absorption of thyroid hormones, also favoring a prompt (immediate) release formulation for better clinical outcome.
Another compounding option is Thyroid USP from desiccated porcine thyroid gland, which contains both T4 and T3 along with calcitonin and iodine in trace amounts. This full complement of hormones is favored by some patients for symptomatic control. The ratio of T4 to T3 in porcine thyroid is roughly 4.2:1. Immediate-release capsule formulas are the most commonly compounded.
An important note with either disease: when a patient’s thyroid levels and subsequent symptoms get to the point where TRT is needed, addressing the underlying autoimmune disease has probably not been done! Although the patient is getting thyroid hormones, the immune system has not been corrected. So how do we address this?
There is much evidence that gut dysbacteriosis, bacterial overgrowth and increased gut permeability favor the development of HT, and it has been suggested that the thyroid–gut axis may influence our overall metabolism.6,7 In addition, the results of a recent meta-analysis investigating the effect of a gluten-free diet (GFD) seem to indicate a positive effect on thyroid function and its inflammation, particularly in patients with HT.7
As such, you may want to advise TRT patients to avoid proinflammatory foods such as gluten and implement gut restoration protocols — including probiotics — to reinoculate the intestines. Healing the lining with supplements such as L-glutamine could also have positive effects on clinical outcome. In addition, low-dose naltrexone (LDN) therapy is a good way to help correct GI inflammation and improve immune function.
Maintaining appropriate thyroid levels in TRT patients can be tricky, even overwhelming. Members with clinical services may contact our Clinical Services team for help with dosage recommendations, lab interpretations and other concerns.