Thyroid medications are amongst the most commonly prescribed medications in the world. In fact, in Canada, thyroid medication is the 3rd most commonly prescribed drug behind anti-depressants and lipid lowering agents in women  (thyroid disease is more common in women than men). Given the fact these medications are used so much – patients and doctors are often met with a common scenario: the lab values simply don’t correlate to how the patient feels, even during thyroid hormone therapy.
Normal Thyroid Function
We often use certain lab measures to assess thyroid function. To review the basic anatomy, physiology and routine lab work, please click here.
As a quick reminder, we typically look at TSH, and sometimes T4, and maybe T3 in the blood. Their relationship is supposed to tell us if the thyroid is under-functioning, over-functioning or working optimally . Oftentimes the lab values relate perfectly with the patients signs and symptoms. However, we regularly find the lab work doesn’t make sense for one reason or another , . An article on confusing thyroid blood work can be accessed by clicking here.
What is Levothyroxine?
As a reminder, T4 is one of the thyroid hormones the thyroid gland releases. T4 needs to be converted to T3 to have biological activity. The other chemical name for T4 is thyroxine. Levothyroxine is a synthetic form of T4, prescribed to patients with low functioning thyroid glands. Levothyroxine is the generic name; brand names you may recognize are Synthroid and Eltroxin . We also refer to Levothyroxine as L-T4 for short – as I will do for the remainder of this article.
How Dose is Determined
Remember, Levothyroxine (L-T4) is given by doctors when TSH is high and T4 and or T3 are low. Doctors will determine the optimal dose by aiming to ‘normalize’ these numbers. Doctors will have targets for each lab value and tests should be done every 2-3 months until the correct dose has been determined. Once dose is determined, yearly check- ins are all that’s needed. Most patients feel better once T4 is in the upper half of normal range (110-165 nmol/L) .
Sometimes Lab Values May Not Correlate to Symptoms
Often a source of confusion, patients on Levothyroxine (L-T4) may not get the changes they expect. Oftentimes, blood work reflects improvement, yet the patient experiences same (or worse) symptoms of hypothyroidism. How should this be treated? Should dose be adjusted? What are a patient and doctor to do in this scenario?
Anomalous Blood Work with Levothyroxine Therapy
Expectations of Levothyroxine Therapy
We generally expect TSH to drop, T4 and T3 to normalize. Symptoms should subside.
It should be noted, that it is also normal for someone on thyroxine replacement at normal physiological dosage to normalize TSH levels and get mildly elevated free T4 but normal Free T3 .
TSH: normal FT4: mildly ↑ or normal
- Normal physiological variant: To abolish symptoms and normalise TSH concentrations, some individuals exhibit mildly elevated FT4 (possibly reflecting less efficient conversion of T4 to T3); free T3 is typically normal , 
Common Causes of Confusing Thyroid Blood Work for Someone on Levothyroxine (L-T4)
TSH: ↑ FT4:↓ (or low end of normal)
- Maladministration: L-T4 should be taken on an empty stomach, , ; certain foodstuff (e.g. fibre, coffee) and some medications (e.g. iron, calcium, PPIs, sucralfate, aluminium hydroxide, cholestyramine) may impair L-T4 absorption
- Malabsorption syndromes: L-T4 malabsorption occurs with various gastrointestinal conditions, such as celiac disease, achlorhydria, lactose intolerance (lactose is a constituent of some L-T4 preparations) , ,
- Increased thyroid hormone (T3 and T4) metabolism or excretion: Many factors increase L-T4 requirements by enhancing the liver metabolism of thyroid hormone, , . For more information check out this article, here.
- Increased thyroid hormone binding capacity: Oral estrogen therapy or gonadotrophin-induced rise in estrogen concentrations (e.g. IVF treatment) results in a marked increase in thyroid binding globulins and hence thyroid hormone binding capacity, necessitating an increase in L-T4 therapy; similar effects are seen with SERMs and mitotane , ,
Unexpected change in L-T4 dosage requirements to maintain clinical and biochemical euthyroidism
- Change in LT4 preparation: There are various L-T4 preparations. They differ in potency and bioavailability. Changes in preparation are generally best avoided but, if necessary, should prompt more frequent blood testing monitoring , ,
TSH: ↑ FT4: Normal
- TSH assay interference: Heterophilic antibody interference in the TSH assay may yield falsely elevated results; FT3 is normal  , 
Persistent ↑TSH, with ↓, ↑ or normal FT4, despite treatment with high L-T4 dosages
- Poor compliance: Owing to their differing half-lives, intermittent thyroxine ingestion may result in normal or even elevated thyroid hormone concentrations, but fails to normalize TSH  , 
Supraphysiologic L-T4 required to normalize TSH, but with resultant ↑FT4 (and ↑FT3)
- Resistance to thyroid hormone: Typically seen following inappropriate thyroid ablation or concomitant primary hypothyroidism in a patient with a genetic mutation in the human thyroid hormone receptor β (THRB) gene  , 
As you can see, there are many factors that go into L-T4 metabolism, excretion and utilization. This information is not intended to provide a template for dosing adjustments; it is merely to inform patients and doctors alike that these factors all play a role and potentially complicate blood testing associated with thyroid health. If you fall under one of these categories, please see you primary care physician to discuss.
About the Author
I'm Johann de Chickera, a Naturopathic Doctor, practicing in Ontario, Canada. My clinical practice relies on keeping up with the most up-to-date research and continued education. This blog serves as a way to provide others with a compilation of everything I've learned along the way. Please click here if you're local and want to see me in practice.