Equivalence between liothyronine (T3) and levothyroxine (T4) therapy

pharmacokinetics of thyroid hormones (1)

• oral T4 (thyroxine)
  • when T4 is taken orally, up to 80% of it is absorbed, and the peak serum concentration is reached two to four hours after ingestion
  • serum concentration then rises by 20% to 40%
  • half-life of T4 is relatively long, at 190 hours
  • a fatty meal lowers its absorption by 40% , and even drinking coffee lowers its absorption by 27% to 36%
  • consequently, thyroid hormone must be taken in the fasting state, with water, 30 to 60 minutes before breakfast
    
    
• oral T3 (triidothyronine, liothyronine)
  • absorption of T3 is 90%, and peak levels are reached one to two hours after ingestion
  • serum concentration may rise by 250% to 600%
  • T3 has a relatively short half-life of only 19 hours

UK guidance states (2):

• in most circumstances, the primary care prescribing of liothyronine (T3) is not supported for any patient. Initiation for patients with hypothyroidism should only be undertaken by consultant NHS endocrinologists. This advice applies to both liothyronine monotherapy and combination therapy with levothyroxine (T4)
  • however "...recognised that a small number of patients may have persistent symptoms of hypothyroidism despite adequate replacement using levothyroxine, evidenced biochemically by serum Thyroid Stimulating Hormone (TSH) being between 0.4 - 1.5mU/L. As part of the overall holistic management of these patients, consultant NHS endocrinologists may start a trial of combination levothyroxine and liothyronine in order to restore wellbeing in circumstances where other potential causes of symptoms have been excluded and all other treatment options have been exhausted..."
    
    
• if a patient is ever initiated on treatment, prescribing responsibility should remain with the hospital consultant for at least 3 months
  • TSH levels should be monitored during treatment to reduce the risk of over- or under-treatment, and free T4 / free T3 levels measured where clinically appropriate
  • risks of over-treatment include atrial fibrillation, osteoporosis and bone fractures

Prescribing of Liothyronine in Endocrinology: Hypothyroidism

• Liothyronine Monotherapy
  
  
  • the RMOC has considered on-going prescribing of liothyronine and advises the following:
    • Liothyronine monotherapy is not recommended in hypothyroidism; prescribing would be in exceptional circumstances only, such as clearly distinguishable specific levothyroxine medication intolerance including extremely rare cases of levothyroxine induced liver injury. Or potentially for patients who do not effectively metabolise levothyroxine to liothyronine, if a specialist assessing the patient according to these guidelines agrees
      
      
    • In accordance with NHS guidance on 'Defining the Boundaries between NHS and Private Healthcare', patients who are currently obtaining supplies via private prescription or self-funding should not be offered NHS prescribing unless the guidelines in this document are met. Patients who have been seen privately retain the option of being referred back to the private service for private prescription
      
      
    • Individuals currently prescribed liothyronine for hypothyroidism are to be referred to a consultant NHS endocrinologist to consider transition to levothyroxine through a trial titration where clinically appropriate
      
      
    • The consultant NHS endocrinologist should identify when and why liothyronine was initiated, and must specifically define the reason if any patient currently taking liothyronine should not undergo a trial titration to levothyroxine; this is to be communicated to the GP
      
      
    • If a previous trial titration has proved unsuccessful, the consultant endocrinologist should decide whether there is any good reason to consider a further review, and inform the GP accordingly
      
      
    • The review of NHS patients presently receiving liothyronine is to be managed locally and scheduled according to service capacity. Local commissioners should consider providing advice to GPs to support the gradual conversion of current patients to levothyroxine, where clinically appropriate, with NHS endocrinologist support, and with appropriate arrangements for endocrinologist review
      
      
    • The abrupt withdrawal of liothyronine therapy from patients who have been stabilised on treatment for hypothyroidism is inappropriate
      
      
    • Treatment changes are to be under consultant NHS endocrinologist review or in circumstances where a GP is fully supported by a consultant NHS endocrinologist
      
      
    • Where liothyronine is prescribed, GP repeat prescribing would be reasonable after completion of a 3 month or longer review by an NHS consultant endocrinologist
      
      
    • Where liothyronine is so prescribed, prescribers and commissioners should consider the most appropriate means of meeting the patients' needs, and any arrangements for shared care are to be agreed within the local health economy
      
      
    • All shared care arrangements are to be authorised by the local commissioner
• Hypothyroidism
  • Combination Levothyroxine and Liothyronine
    • General Guidance:
      • The guidance above for liothyronine monotherapy is also applicable when a patient converts to combination therapy
        
        
      • Combination levothyroxine / liothyronine should not be used routinely in the management of hypothyroidism as there is insufficient population based clinical evidence to show that combination therapy is superior to levothyroxine monotherapy
        
        
      • There is insufficient evidence at present to specify the quality of life measures to be adopted during a trial of combination levothyroxine and liothyronine, or during a trial titration from liothyronine to levothyroxine. Further work is ongoing to develop a validated quality of life measurement tool in advance of the NICE thyroid disease guidelines planned for release in 2019. In the interim, NHS consultant endocrinologists should document the range and severity of hypothyroid symptoms experienced by the patient prior to and during the assessment period
        
        
      • Specialist endocrinology oversight therefore requires review of both blood biochemistry and patient symptoms as recommended by the British Thyroid Association Executive Committee

Notes:

• equivalence between liothyronine (l-T3) and levothyroxine (l-T4) therapy
  • consult expert advice
    • a study investigated the equivalency between l-T3 and l-T4 therapy measured by baseline and TRH-stimulated TSH
      • the therapeutic substitution of l-T3 for l-T4 was achieved at approximately 1:3 ratio (4)
    • however UK guidance states (1) there is no defined conversion factor, and conversion of patients from liothyronine to levothyroxine monotherapy will require a reduction in the dose of liothyronine and an increase in levothyroxine. A reduction of dose of liothyronine by 10 micrograms will probably require an increase in dose of levothyroxine of 50 micrograms. Once on levothyroxine monotherapy, patients will need to have adjustment in the dose as per standard practice by monitoring of the TSH on a 6 weekly basis. Blood tests should not be undertaken more often than 6 weekly because the TSH will not have reached steady state until 6 weeks after any change. Free T4 / free T3 levels should also be measured where clinically appropriate
      
      
• giving T3 for replacement is unphysiological and less well tolerated and is thus not recommended as a routine measure (1)
  • mono-deiodization of T4 normally occurs as needed in the peripheral tissues, so that there is no need to take T3 (liothyronine) as well
    
    
• thyroid gland produces predominantly T4 with a small amount of T3
  • about 85% of circulating T3 is the result of monodeiodination of T4 in the tissues, especially the liver, muscle and kidney
  • T3 is about five times more active than T4
  • majority of T3 and T4 is carried in the plasma bound to thyroxine binding globulin, TBG, thyroxine binding pre-albumin, TBPA, and albumin. However, unbound T3 and T4 are the active forms and gain entry into the cell by an ATP dependent process
  • production of T3 and T4 is controlled primarily, by the circulating concentrations of free thyroid hormone which exert a negative feedback on TSH release. However, dopamine, somatostatin and glucocorticoids may reduce plasma TSH and so affect TSH release
    
    
• when combination therapy with T3 and T4 may be appropriate
  • if the clinical manifestations of hypothyroidism persist under L-thyroxine replacement therapy despite normalized TSH levels, this may be due to genetic variation (1) in the peripheral 5' - deiodinases, which are selenoprotein enzymes that catalyze the conversion of T4 to active T3 as needed
    • patients with low peripheral 5' - deiodinase activity may be unable to metabolize T4 to T3 in adequate amounts and may therefore respond better to combined replacement therapy than to T4 alone
    • no routinely available clinical biochemical or genetic test to determine whether this is the case

Reference:

• Schäffler A.Hormone replacement after thyroid and parathyroid surgery.Dtsch Arztebl Int. 2010 Nov;107(47):827-34
• Regional Medicines Optimisation Committee (RMOC) (July 2019). Guidance - Prescribing of Liothyronine
• Celi FS et al. The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross-over study in thyroidectomized patients.Clin Endocrinol (Oxf). 2010 May;72(5):709-15