Current approach to therapy; benefits and potential shortfalls

Since the 1970s, levothyroxine (LT4) has been the mainstay in the treatment of hypothyroidism. This is primarily because of predictable manufacturing that is regulated by the United States Food and Drug Administration (FDA) and one dose a day is enough to normalize thyroid hormone levels for the majority of patients.

Unfortunately, approximately 15% of adult patients who take LT4 only (monotherapy) report persistent hypothyroidism symptoms despite having normal thyroid stimulating hormone (TSH) and thyroxine (T4) levels. For adults, the most common reported signs and symptoms include decreased ability to focus or concentrate (brain fog), fatigue, decreased energy, depressed mood, change in metabolism associated with a decreased ability to lose weight or an increased likelihood of gaining weight, and overall lower quality-of-life scores.

As all of us are aware, these symptoms are not specific and they are common. Multiple factors of daily life come into play, including increased workload, increased pressures from school and work, poor sleep hygiene (decreased number of hours of sleep per night and late bedtimes), and social stress.

In pediatrics, there are limited published data on the topic of “persistent signs and symptoms consistent with hypothyroidism despite normal TSH,” but in CHOP’s Pediatric Thyroid Center, we see children with similar symptoms — such as fatigue, brain fog, constipation, dry skin, brittle nails, cold intolerance and others — even when their TSH and T4 levels are normal. The situation clearly exists, and the normal stress of growth and development can exaggerate signs and symptoms.

The role of triiodothyronine (T3)

Over the last two decades, there is increased awareness of the potential importance of triiodothyronine (T3) levels in patients on LT4 monotherapy. Thyroxine (T4) is a prohormone, and our body converts T4 to T3, the active form of thyroid hormone. T3 is not used as a replacement medication because current LT3 drug formulations are associated with a short half-life in our bloodstream, estimated at five to six hours for T3 compared to five to six days for T4. That means current formulations of T3 require that patients take a dose two to three times a day to maintain stable levels in the body.

In patients with an intact, normally functioning thyroid gland, the body produces enough T3 to maintain normal T3 levels. However, approximately 10% to 15% of adult patients who are on LT4 monotherapy cannot achieve a normal T3 level. In these patients, the T3 level is either below the normal range or in the lower end of the normal range even when the T4 level is at or above the normal range. Why this occurs is not completely known, however, current data supports that these patients do not efficiently convert the T4 to T3 to maintain normal T3 levels.

In adult patients, there is conflicting data on whether placing patients on combined T4 and T3 therapy improves quality of life and decreases the “brain fog” that patients report. Because of consistent data showing clinical improvement for all patients and the requirement to take T3 several times a day, many endocrinologists do not evaluate T3 levels or consider using combined LT4 and LT3 therapy.

Adding liothyronine (LT3)

At the CHOP Pediatric Thyroid Center, we feel there is a benefit to monitoring T3 in addition to TSH and free T4 in children on thyroid hormone replacement therapy. For children exhibiting hypothyroid symptoms even when they have normal TSH and free T4 levels when they are on LT4 monotherapy, we believe combination therapy with levothyroxine (LT4) with liothyronine (LT3) may be considered based on our assessment of the child’s T3 levels and in discussion with the patient and care-provider(s).

The goal of combination therapy is to move all thyroid hormone levels into the normal range, including TSH, T3 and T4. By doing this, some children report a decrease in hypothyroid symptoms; specifically they say they have an increased ability to focus as well as have improved energy and mood. Because positive results of combined therapy are not guaranteed for every patient, if the signs/symptoms do not improve patients can be moved back to LT4 monotherapy.

Criteria for combined therapy

For a child being considered for combined LT3 and LT4 therapy, addressing the other factors — most importantly optimizing diet, exercise and sleep hygiene — are critical. In addition, for children with depressed mood, an important part of the treatment plan is for them to be evaluated and potentially treated for a behavioral mood disorder to increase the chance for positive change.

If your child is experiencing hypothyroid symptoms on levothyroxine (LT4) monotherapy, combined LT4/LT3 therapy may be worth exploring. When administered and monitored by an experienced team that is proficient in combination therapy, it is safe and comes with little risk. If you feel your child is eligible, please contact our team to discuss next steps.

Children on combined LT3 and LT4 therapy will continue to be monitored by regular blood work. Lab results will determine if levels of LT4 and LT3 will be adjusted.

Brand name vs. generic forms of replacement hormones

Most children treated with levothyroxine (LT4) for hypothyroidism do very well on the generic form, levothyroxine. This is supported by the resolution of hypothyroid symptoms (fatigue, brain fog, constipation, cold intolerance, dry skin, brittle nails) as well as by the normalization of thyroid function tests.

However, there are a handful of patients who experience better control and feel better on the brand name thyroid hormone replacement Synthroid®. These patients may experience an improvement or resolution of symptoms, and/or normalization of thyroid function tests, which were not able to be normalized on generic levothyroxine.

There are several reasons why patients may do better on brand name vs. generic levothyroxine as well as different formulations, including tablet vs. gelcap vs. solution (NOT suspension). One of the main reasons for differences between brand vs. generic is based on how the U.S. FDA defines differences in bioequivalence within the same manufacturer compared to between different manufacturers of LT4. Based on the FDA, the concentration of LT4 between different generic versions of the same dose can be up to a 12.5% different between manufactures but must be within 5% different within the same manufacturer. So, it is not that one form is “better” than the next, but that the consistency of dosing is better within a manufacturer and that when you are prescribed “brand name,” the pharmacy must give you the specific brand rather than relying on the supply chain that may deliver medication from one of several different manufacturers that produce LT4.

How this could impact your dosing is best considered as an example. If you are prescribed generic levothyroxine 100 mcg daily, the dose could be (could, not that it will be) between 88 mcg and 112 mcg between different generic manufacturers (up to 12.5% different). If the same generic manufacturer supplies your pharmacy, then the difference between batches would be consistent, up to 5%, or between 95 mcg and 105 mcg per tablet. In contrast, if you are prescribed the brand name LT4, the potential 12.5% variation between manufacturers is eliminated as the pharmacy will only prescribe from one company.

Reducing the potential differences in bioequivalence by moving from generic to brand name may help patients who are exhibiting continued signs and symptoms and/or whose thyroid function tests are not easily normalized despite addressing the other issues that impact health and well-being, including compliance with medication, sleep hygiene, healthy diet, exercise and other medical diagnoses.

In infants and toddlers with congenital hypothyroidism (CH), the brand name is often recommended to reduce the potential differences in dose amount, which may be more impactful during a time of rapid growth and development. 

Desiccated thyroid hormone

Desiccated thyroid hormone replacement, or thyroid hormone that is made from animal thyroid glands, are natural forms of thyroid hormone replacement that were used prior to wide availability of synthetic LT4 in the 1970s. While there does not appear to be an advantage in using a “natural” vs. a “synthetic” form of thyroid hormone, one advantage of desiccated thyroid hormone is that it contains both T4 and T3 in a mostly fixed ratio of approximately 4:1. The potential disadvantage of desiccated thyroid hormone replacement are three-fold:

First, the ratio of T4:T3 in a pig thyroid is about 3 to 4 fold different compared to a human thyroid, with a pig thyroid having 4:1 of T4 to T3 and a human thyroid having a ratio of about 15:1 to 20:1. So, there is more T3 in a pig thyroid than in a human thyroid.

Second, the ratio in the pig thyroid is fixed. We cannot independently adjust the T4 or T3 amount. As an example, one of the prescribed versions of desiccated thyroid has 38 mcg of T4 and 9 mcg of T3 per grain. If a patient requires a higher dose of LT4 but not LT3, there is not a way to increase the amount of LT4 without adding a synthetic tablet of LT4.

Thirdly, the regulation of desiccated thyroid is not as closely monitored by the U.S. FDA because the drugs were brought to market prior to publication of the 1962 U.S. FDA regulation that defines drug bioequivalence. Based on these facts, if a patient is going to be tried on combined LT4 and LT3 therapy, it is easier to prescribe separate, synthetic LT4 and LT3 tablets so that each form can be tailored to meet an individual patients’ needs in an effort to optimize thyroid hormone levels.