Liothyronine

Liothyronine is a synthetic form of thyroid hormone (T3, triiodothyronine) that may be used to treat hypothyroidism and myxedema coma. It is also used as an augmentation strategy in treating Major Depressive Disorder when used in combination with antidepressants." "Physicians may use liothyronine instead of or in addition to levothyroxine (T4) for patients undergoing thyroid hormone withdrawal." (Wikipedia).

Liothyronine treatment has mainly been considered for

• 1) genetic polymorphisms, especially in the DIO genes, that may hinder T4-T3 conversion and are associated with risk for various diseases (But the use of L-T3 to treat conditions attributed to genetic polymorphisms has not yet been explored as of 2016)
• 2) Low-T3 syndrome in hospitalized patients with normal thyroid glands. (But clinical trials using L-T3 in various treatment modalities have been inconclusive).
• 3) treatment for hypothyroidism, especially in cases where hypothyroid symptoms persist despite normal TSH on L-T4 monotherapy. (However, this has been very controversial, and researchers have used a wide variety of methods and T3/T4 treatment modalities, making it difficult to conduct meta-analyses.)

1. GENETIC POLYMORPHISMS

Health risks are associated with polymorphisms in two genes responsible for T4-T3 conversion: liothyronine deiodinase 1 (DIO1), and 2 (DIO2). Reduced T4-T3 conversion may be in part responsible for risks associated with osteoarthritis [PMID 22492780] [PMID 18334578], depression [PMID 21563302], [PMID 26098717], bipolar disorder [PMID 19427350], malignancy in cancer [PMID 25944909]

[PMID 27982198] (Published 2016). "Treatment of hypothyroidism with levothyroxine plus liothyronine: a randomized, double-blind, crossover study." "Despite the fact that our study and previous meta-analyses failed to find clear benefits in the treatment of hypothyroid individuals with combination LT4/LT3, it is possible that a subgroup of patients with deiodinase 2 (DIO2) polymorphisms can benefit from combination therapy (43). One such polymorphism in the D2 gene (Th92Ala) is associated with reduced T4 to T3 activation in skeletal muscle and thyroid, as well as alterations in thyroid–pituitary feedback. A suggestive indication to the presence of this polymorphism could be a higher-than-normal ratio of free T4 to free T3 (6,44). Other polymorphisms in the phosphodiesterase 8B (PDE8B) may also alter the carrier’s genetically determined TSH set-point, leading to sustained hypothyroid symptoms despite normal TSH levels (7). To date, it is still unclear whether polymorphisms play a role in response to therapy in patients with hypothyroidism."

[PMID 19190113] According to a 2009 study of 500 patients, hypothyroid patients on LT4 (Levothyroxine) therapy who don't show much improvement may have lower brain thyroid levels (not reflected in their serum levels) correlated to the number of rs225014 (C) alleles they carry, and these patients may benefit from combined levothyroxine and liothyronine therapy.

[PMID 26010808] A June 2016 statement by the British Thyroid Association cited the American Thyroid Association (ATA) as stating "Currently, genetic testing is not recommended as a guide to selecting therapy for 3 reasons.

• (i) Although there are data suggesting that specific polymorphisms of the type 2 deiodinase gene might be associated with therapeutic response to combination synthetic L-T3 and L-T4 therapy, controlled confirmatory studies are needed.
• (ii) Currently, genetic testing for these specific deiodinase polymorphisms is only available in the research setting.
• (iii) The small effect of the type 2 deiodinase gene variants identified so far that do affect thyroid hormone concentrations suggests that other factors (e.g. yet unidentified genetic variants) may play a far greater role in determining an individual patient's thyroid hormone concentrations."

2. LOW T3 SYNDROME

In cases of acute illness and hospitalization, patients with normal thyroid glands occasionally fall into a state of Low T3 levels and high Reverse T3 (rT3) levels, nonthyroidal illness syndrome (a.k.a. Low T3 syndrome, consumptive hypothyroidism). Researchers have theorized that this is largely due to overexpression of Deiodinase type 3 DIO3 and reduced expression of DIO1 and/or DIO2 [PMID 24845024].

Although researchers have debated whether Low T3 is an adaptive or pathological state during severe illness, Low T3 syndrome has significant risk of adverse outcomes, especially in cases of cardiac injury, heart disease, and kidney disease [PMID 26379043], [PMID 21415143], [PMID 24574542].

However, some randomized trials of L-T3 therapy in Low T3 patients have yielded contradictory results ([PMID 18171701] versus [PMID 25359424]), possibly due to their different treatment modalities and perhaps confounding variables.

3. ALTERNATIVE, CONTROVERSIAL TREATMENT FOR HYPOTHYROIDISM

Research has shown that hypothyroid patients on L-T4 therapy alone typically have significantly higher T4, higher TSH and lower T3 levels serum than healthy controls, regardless of genetic polymorphisms ([PMID 18492748]. Similarly, lower T3 and higher reverse T3 is common in thyroid cancer patients receiving high doses of L-T4 in order to suppress TSH [PMID 22017394].

However, the use of L-T3 & L-T4 combination therapy for hypothyroidism has been controversial. L-T3 therapy alone is rarely attempted or studied because it is considered to be unnatural, given that a healthy thyroid gland produces approximately 80% T4 and 20% T3. Many endocrinology organizations and government health organizations have recommended against the use of L-T3 in hypothyroidism, partly for economic and practical reasons, but largely due to doubts of its having any greater efficacy than the standard treatment of L-T4.

[PMID 21865366] Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine. (Published 2011). Concluded "The substitution of L-T(3) for L-T(4) at equivalent doses (relative to the pituitary) reduced body weight and resulted in greater thyroid hormone action on the lipid metabolism, without detected differences in cardiovascular function or insulin sensitivity." (Abstract)

[PMID 26940864] A 2016 study, "Liothyronine use in a 17 year observational population-based study - the tears study" compared 400 patients who had ever used liothyronine with 955 patients who had never used liothyronine. Among the 400 patients who had received prescriptions for liothyronine, 327 received liothyronine (L-T3) in combination with l-thyroxine (L-T4), and 73 had received liothyronine only. The median duration of time on L-T3 therapy was 10.9 years and on L-T4 alone was 8.3 years. The mean follow up was 9.3 years, maximum 17.3 years. The most significant results (from Table 2):

• Diabetes: L-T3 patients 3.5%, L-T4 patients 7.3% (p = 0.004) L-T3 HR
• Thyroid cancer: L-T3 21.8%, L-T4 0.4% (p = 0.001)
• Thyroid surgery: L-T3 9.8%, L-T4 0.2% (p = 0.001)
• Antipsychotic medication: L-T3 10.0%, L-T4 4.4% (p = 0.001)
• Antidepressant medication: L-T3 30.3%, L-T4 21.3% (p = 0.001)
• Statin medication: L-T3 4.5%, L-T4 12.0% (p = 0.001)

Hazard Ratios for patients who had ever used L-T3, compared with patients on L-T4 only (1.00), after adjustment for history of relevant diseases and medications (from Table 3):

• Bone fractures 0.792
• Atrial fibrillation 0.911
• Non-fatal cardiovascular disease 1.04
• Breast cancer 1.754
• Diabetes mellitus 0.828
• Mental disorder 1.558
• Death 0.771

[PMID 23974776] Combination L-T3 and L-T4 therapy for hypothyroidism. (Published 2013.) "Although our professional organizations continue to recommend L-T4 alone for the treatment of hypothyroidism, the possibility of a D2 gene polymorphism should be considered in patients on L-T4 monotherapy who continue to complain of fatigue in spite of dosage achieving low normal serum thyroid stimulating hormone levels. A suggestive clue to the presence of this polymorphism could be a higher than normal free T4/free T3 ratio. Clinicians could consider adding T3 as a therapeutic trial in selected patients. Future well controlled clinical trials will be required to more fully resolve the controversy." (Abstract)

[PMID 24419358] "Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism." (Published 2014). The review explained that "Evidence is mounting that levothyroxine monotherapy cannot assure a euthyroid state in all tissues simultaneously, and that normal serum TSH levels in patients receiving levothyroxine reflect pituitary euthyroidism alone." Genetic polymorphisms in thyroid hormone transporters and deiodinases may contribute to insufficient T3 at a cellular level. "Levothyroxine monotherapy remains the standard treatment for hypothyroidism. However, in selected patients, new guidelines suggest that experimental combination therapy might be considered." (Abstract).

[PMID 26544166] A 2016 article titled "Update on the Treatment of Hypothyroidism" stated that "Multiple studies of combination therapy with levothyroxine and liothyronine for treating hypothyroidism have not led to a clear conclusion about its benefits over levothyroxine monotherapy."

The use of combination therapy has been questioned by the American Thyroid Association (ATA) and the European Thyroid Association (ETA)

• 2012 ETA guidelines [PMID 24782999]
• In response to the guidelines, a 2015 review on L-T3 and L-T4 therapy at [PMID 26654514]) concluded "This systematic review illustrates that clinical practice guidelines worldwide do not recommend and do not support routine use of combination LT4 and LT3 therapy to treat hypothyroidism."