Hypothyroidism Treatment-Levothyroxine (T4) And Liothyronine (T3)-From Dr. Mandel And The Curbsiders

In addition to this post, please see Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014)
Jonklaas, Bianco, et al., Thyroid 24(12): 1670-1751, 2014

In this post I link to and excerpt the Curbsiders’ section on “Hypothyroidism Treatment” from #208 Hypothyroidism Master Class with Susan Mandel MD, MPH. APRIL 20, 2020 By DR ELENA GIBSON

Here are the excerpts:

Hypothyroidism Treatment

Levothyroxine provides T4 replacement and is the treatment of choice for hypothyroidism. The thyroid makes two thyroid hormones T4 and T3,  named for the number of iodine molecules they contain (T4 has 4 and T3 has 3). T3 is the active hormone that enters the nucleus of cells and activates hormone receptor genes (Jonklaas 2014). Provided the body has sufficient iodine, the thyroid alone makes 100% of T4 and ~20% of T3. Although levothyroxine does not replace the 20% of T3 from the thyroid, the remaining ~80% of T3 is made in the liver or elsewhere in the body where enzymes remove an iodine from T4 to make active T3 (Jonklaas 2014).


In a young healthy patient (overt or subclinical hypothyroidism), start levothyroxine at a full treatment dose of 1.6ug/kg (Jonklaas 2014). In patients with an elevated BMI, consider a dose reduction as recent data suggests a need to dose more towards ideal body weight (Papoian 2019). In elderly the metabolism of thyroid hormone slows down, so lower doses are frequently required (Jonklaas 2014). For patients over 65 to 70 years old, Dr. Mandel recommends treatment should “start low and go slow” unless the patient requires full supplementation following a thyroidectomy. Start low at 25-50mcg (25mcg if cardiovascular disease) then increase by small increments of 12.5 to 25mcg with a target TSH in the high/normal range of 4-6. Cautious escalation of therapy should also be considered in patients with a history of cardiac disease to avoid precipitating angina.

Initial Dosing:

Seventy five percent of oral thyroid hormone is absorbed under normal conditions, and various factors can interfere with thyroid absorption. Iron supplements, soy protein, multivitamins, prenatal vitamins will decrease thyroid hormone absorption. Given the 7 day half life of levothyroxine, the medication can be taken at any time of day, including at night before sleeping. Data supports that the medication will be absorbed well as long as it is taken 3 hours before or after a meal, and Dr. Mandel reinforces how consistency is the most important factor (Jonklaas 2014). Although meals can interfere with absorption, if the same type of meal is eaten around the time of the levothyroxine, the dosing shouldn’t require as much adjustment. Problems are more likely to occur with changes in dietary patterns such as new intermittent fasting. In lower resource settings levothyroxine can even be dosed once per week (Jonklaas 2014). However, this can lead to additional issues with taking high doses infrequently, and it is not as physiologic.

Kashlak Pearl: Levothyroxine will be absorbed well as long as it is taken 3 hours before or after a meal. That said, patients’ quality of life is paramount and Dr. Mandel reinforces how consistency is the most important factor (e.g. take it 30 minutes before breakfast everyday).


When initiating levothyroxine treatment, Dr. Mandel reviews how the medication will not work like acetaminophen or ibuprofen. Patients should not expect to feel better in hours, days or even two weeks because the half life is 7 days long. A repeat TSH is checked at 6 weeks because when the thyroid hormone reaches equilibrium (Jonklaas 2014).

Kashlak Pearl: Dr. Mandel has noticed that the resolution of symptoms from hypothyroidism usually lags behind TSH normalization by 2 to 3 months.

Manufacturer differences:

The  FDA determines equivalency by looking at the area under the curve and time to maximal concentration of two thyroid hormone replacement medications, and they are deemed equivalent. However, problems arise in practice as clinical adequacy is determined  by measuring TSH levels, not medication levels. Therefore, if a patient switches from one brand to another, it is recommended to recheck a TSH level to ensure appropriate treatment (Jonklaas 2014). As generics are determined by pharmacy contracts, Dr. Mandel asks patients to call for a TSH check if they notice a difference in the shape/color of  their levothyroxine pill. For most patients with hypothyroidism, this probably isn’t a huge deal because it might be the difference between a TSH of 0.8 and 3,  but worrisome problems may arise in patients requiring more narrow control of TSH, such as patients with thyroid cancer (Jonklaas 2014).

Kashlak Pearl: Dr. Mandel asks patients to call for a TSH check if they notice a difference in the shape/color of  their levothyroxine pill.

Treating to TSH 

The distribution TSH levels in euthryoid individuals used to establish a normal reference range (usually 0.4-4.0mIU/L) is not a bell shaped curve, and 95% of patients have TSH levels <2.5 mIU/L (Razvi 2019). Therefore, clinicians have historically aimed for a TSH in the lower range of normal, but no clear benefit has been associated with adjusting treatment to lower TSH goals in current literature (Jonklaas 2014). One cross-over study by Walsch et al. found no difference in patient reported symptoms between different treatment doses resulting in three different mean TSH levels within the reference range (Walsch 2006). Similarly a randomized trial by Samuels et al. of treatment to lower half, upper half and above normal reference range TSH goals did not identify a relationship with TSH level and quality of life,mood or cognition (Samuels 2018). Although the evidence does not support lower TSH goals, Dr. Mandel aims for a goal TSH of 0.5-3.0 in most patients, due to anecdotal evidence of improved symptoms and TSH levels seen in euthyroid patients. Excessive levothyroxine can lead to iatrogenic hyperthyroidism (TSH below normal reference range), and should be avoided due to increased risk of fracture and atrial fibrillation (Jonklaas 2014). Some guidelines recommend treating to a higher TSH goal of 4-6 in patients >70 years old (Jonklaas 2014).

The TSH should be checked every 6 weeks while titrating a dose and yearly to ensure appropriate dosing after a treatment dose is established (Jonklaas 2014).

T3 Testing and Treatment 

With new T3 products available many patients ask about the utility of T3 testing and replacement.

T3 Testing

When asked about T3 testing, Dr. Mandel discusses the importance of considering how T3 production changes with demand.  Throughout the day, T4 is converted to T3 on an as needed basis. Dr. Mandel explains how T3 levels in the morning after fasting or after running are very low, and levels spike after eating when additional conversion is needed for metabolism. Therefore, a single snapshot of T3 does not provide a true representation of the demand based conversion and homeostasis the body maintains.

Treatment with T3

Most patients do well on levothyroxine alone, and population-level research has not identified any benefit to treating hypothyroidism with levothyroxine (T4) and liothyronine (T3) compared to levothyroxine alone (Jonklaas 2014). However, in Dr. Mandel’s opinion there are some patients that improve when the 20% of T3 made by the thyroid is replaced. Dr. Mandel considers trialing T3 treatment in patients with a TSH in the normal range or lower part of normal with ongoing cognitive symptoms (decreased attention, mental fog), after ruling out sleep disorders. Treating with T3 is challenging because there is no long acting T3 like levothyroxine. Liothyronine (T3) peaks and troughs in 3 hours, so it requires at least twice per day (morning and 2-3pm) dosing and Dr. Mandel recommends avoiding doses of >5mcg at one time. Importantly, levothyroxine (T4) and liothyronine (T3) should be dosed to achieve the physiologic T4:T3 ratio of 14 to 1(Jonklaas 2014). Dr. Mandel advises against using the extract because it has a fixed ratio of 4:1. Additionally, she avoids T3 use in older patients, those with any history of coronary artery disease, and pregnant patients given the potential effects on the heart and inability to cross the placenta.


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