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NHS UKMi – Q&A – 56.6 (Resubmission February 2014) (UD)

What clinical evidence is there to support the use of Armour thyroid or desiccated thyroid extract?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals.

Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: December 2013

Summary

    • Desiccated thyroid extract is derived from porcine thyroid gland. One grain contains 38mcg levothyroxine (T4) and 9mcg liothyronine (T3) per 65mg of the labelled amount of thyroid. Products such as Armour Thyroid, which contain thyroid extract, are not licensed in the UK. These products are licensed in the USA, but because they have not been approved by the US FDA as a new drug, they have not been subjected to clinical effectiveness studies.

 

    • The amount of thyroid hormone in the thyroid gland can vary from animal to animal; the amount of T4and T3 is measured in both the raw material and actual tablets.

 

    • The Royal College of Physicians (RCP) recommend that levothyroxine alone is used in the treatment of hypothyroidism, underactivity of the thyroid gland. The RCP does not recommend the prescribing of additional liothyronine in any form, including Armour Thyroid (desiccated thyroid or thyroid extract); this is inconsistent with normal physiology, has not been unequivocally proven to be of any benefit to patients, and may be harmful.

 

    • Most liothyronine, (80%), is generated from the de-iodination of circulating T4, so a preparation of levothyroxine should provide T3 in a physiological and appropriate concentration.

 

    • The RCP does not recommend the prescribing of desiccated thyroid because this is inconsistent with normal physiology and has not been unequivocally proven to be of any benefit to patients with hypothyroidism.

 

    • There is a lack of good quality evidence to support the use of desiccated thyroid. Studies vary in design, size, duration and outcomes.

 

    • There is only one small randomised, controlled, crossover trial which has compared the efficacy of desiccated thyroid with levothyroxine

 

    • Seventy patients were treated with one treatment for a period of 16 weeks, then crossed over to the other treatment for another 16 weeks. There was no difference in general health and all patients had TSH levels within range.

 

    • Patients who preferred desiccated thyroid (49%) tended to have greater weight loss and improvement in subjective symptoms such as concentration, memory and energy.

 

    • In a retrospective practice-based review, the use of desiccated thyroid improved symptoms in patients who were previously uncontrolled on levothyroxine (median dose 76-100mcg). No dose titration of levothyroxine had been carried out prior to switching to desiccated thyroid to see if a dose increase could help with symptom control.

 

    • There is limited information regarding adverse events. Product information for desiccated thyroid products state that adverse reactions, other than those indicative of hyperthyroidism because of therapeutic overdosage, are rare. In a small study in which 40 patients had their treatment switched to levothyroxine from desiccated thyroid, abnormally high liothyronine concentrations, measured 2-5 hours post-dose was seen in 90% of patients taking 90mg-180mg desiccated thyroid. Most tolerated this well but six patients had symptoms of hyperthyroidism (nervousness, palpitations and tremor post-dose) and benefited from switching to levothyroxine. Abnormally high liothyronine levels were also seen in a smaller (n=21) case series.

 

    • Some patients do request treatment with desiccated thyroid, such as Armour Thyroid because they do not feel as well when treated with levothyroxine, but there is a lack of robust evidence supporting the clinical effectiveness of desiccated thyroid.

Background

Hypothyroidism is underactivity of the thyroid gland. The aim of treatment is to render the patient euthyroid, or with a normal thyroid state.(1) The Royal College of Physicians (RCP) recommend that, due to overwhelming evidence supporting its use, levothyroxine (tetra-iodothyronine, or T4) alone is used in the treatment of hypothyroidism.(1) Levothyroxine has a long half-life (1 week), giving relatively stable blood levels with minimal daily fluctuations in T4. Most liothyronine, T3, (80%), is generated from the de-iodination of circulating T4, so a preparation of levothyroxine should provide T3 in a physiological and appropriate concentration.(2)

The RCP does not recommend the prescribing of additional liothyronine in any form, including Armour Thyroid (desiccated thyroid or thyroid extract); this is inconsistent with normal physiology, has not been unequivocally proven to be of any benefit to patients, and may be harmful.(1) The RCP note that there are risks from T3 therapy, such as osteoporosis and arrhythmias (which can also occur with over-treatment of T4 and that Armour Thyroid contains an excessive amount of T3 in relation to T4.(1)

Desiccated thyroid extracts, such as Armour Thyroid, NP Thyroid and Nature-Thyroid, are natural preparations derived from porcine thyroid glands. One grain of thyroid contains 38micrograms (mcg) levothyroxine and 9mcg liothyronine per 65mg of the labelled amount of thyroid.(3-5) The amount of thyroid hormone in the thyroid gland can vary from animal to animal; the amount of T4 and T3 is measured in both the raw material and actual tablets.(6) These products are not licensed in the UK and while they are available in the US, they have not been approved by the US FDA as new drugs and have therefore not undergone rigorous clinical trials evaluating safety and efficacy.(3-5)

The use of desiccated thyroid is considered by some to be obsolete and is not supported by the RCP due to the lack of supporting validated research in published in peer-reviewed journals.(1;7-10). There is also some concern that symptoms of hyperthyroidism, due to high T3 levels post-dose, can occur.(2;7-9) However, some patients do request treatment with desiccated thyroid, such as Armour Thyroid because they do not feel as well when treated with levothyroxine (11), but are there any robust data to support the clinical effectiveness of desiccated thyroid?

Answer
Few robust studies of desiccated thyroid have been carried out in the last 10 years. Most data are pre-1980, many studies date from the 1950s to 1970s. These tend to be uncontrolled, open-label studies which compared desiccated thyroid with levothyroxine, not in terms of efficacy and safety but comparative potency, speed and duration of action, and effects on serum lipids; these have not been included in this Q&A.(12-15) It is not clear whether studies comparing levothyroxine alone with levothyroxine/T3 combination can be extrapolated to desiccated thyroid. These studies have not been reviewed because they do not provide information supporting the clinical effectiveness of natural desiccated thyroid.

Randomised, double-blind trial
There is only one randomised, prospective, double-blind study comparing the effectiveness of desiccated thyroid extract (DTE) with levothyroxine (n=70). (11) Patients with primary hypothyroidism on a stable dose of levothyroxine were randomised to treatment with either DTE or levothyroxine in identical appearing capsules. Each grain (65mg) of DTE (Armour thyroid) provided 38mcg levothyroxine and 9mcg of liothyronine. The initial desiccated thyroid dose was based on the conversion: 1mg DTE = 1.667mcg levothyroxine. After 6 weeks of study medication, TSH levels were checked and medication adjusted to maintain TSH between 0.5 and 3.0microIU/mL. Once the TSH was within range, medication was continued for at least another 12 weeks. Patients were then crossed over to the other treatment arm for 16 weeks, with TSH checked at 6 weeks as during the first treatment period.

The primary outcome measures were the changes from baseline to endpoint of a number of assessments, including the Thyroid Symptom Questionnaire (TSQ), the quality of life General Health Questionnaire (GHQ), the Wechsler memory scale (WMS-IV) and the Beck Depression Inventory (BDI). The WMS-IV included the auditory memory index (AMI) and the visual working memory index (VWMI). Subgroup analyses were carried out on patients who preferred desiccated thyroid or levothyroxine or who had no preference. A sample size of 67 was required to provide 80% power to detect a difference of 8 points on the TSQ.

    1. Primary outcome measures. Overall, the patients showed no difference in symptom scores, general health questionnaires or neuropsychological testing. During the DTE treatment period, there was a trend towards greater improvements in GHQ-12, TSQ and AMI and there was a reduction of 2.86lb in weight (p<0.001). No study patient had a TSH level outside of the reference range. No adverse events were reported with any of the treatments; both were tolerated equally well. Patients had higher T3 serum levels during the DTE treatment period but no cardiovascular adverse events occurred.

 

    1. Patient preference. At the end of the study, 34 patients (49%) preferred DTE treatment, 13 (19%) preferred levothyroxine and 23 (33%) had no preference. The higher preference for DTE therapy was due to an average 4lb weight loss during the DTE treatment compared with levothyroxine (p<0.001), (note that on average, these patients were 16lbs heavier at baseline than those patients who preferred levothyroxine), and improvements in subjective symptoms such as concentration, memory, sleep, decision-making capability, happiness and energy levels. Patients preferring DTE therapy did better on their neuropsychological measures compared with baseline [TSQ, GHC, WMS-IV and BDI], while those preferring levothyroxine did better only on the WMS-IV.

 

    1. Predictors of preference for DTE. The best predictor for clinical preference for DTE was a lower TSQ score at endpoint. Patients with lower VWMI values on DTE were also more likely to favour DTE.

 

    1. Doses. The mean levothyroxine dose during the study was 119.2mcg and the mean DTE dose was 80.6mcg.

 

      For the patients who preferred DTE treatment, their general well-being and thyroid symptoms were better controlled than with levothyroxine. It is possible that DTE may provide subtle improvements for some patients. The study is limited by its small size, low sensitivity of some of the neuropsychological tests and biochemical measures, no genetic testing for deiodinase polymorphisms and the lack of a washout period, although this may not have been deemed appropriate. Studies with a longer duration are required to clarify the efficacy and safety of desiccated thyroid extract.

Switching from desiccated thyroid to levothyroxine

      Thyroid hormone levels were compared in 40 patients who had their therapy switched from desiccated thyroid to levothyroxine and clinical benefits were assessed.(7) Seventeen patients had been treated for hypothyroidism and 23 patients received thyroid as medical therapy for thyroid gland suppression. The most common desiccated thyroid doses were 120mg-180mg per day (in 36/40 patients), which were switched to 150mcg to 200mcg daily. Serum thyroid hormone levels were measured while the patients were taking desiccated thyroid, and then at least 6 weeks after changing to levothyroxine. The mean T3 levels with desiccated thyroid were significantly higher than with levothyroxine: 289ng/dL vs. 176ng/dL, p

 

      1. When treated with desiccated thyroid, most patients (36/38) had T[3 levels above the normal range and 39/40 had T4 levels in the low normal or normal range; raised T4 level was seen in a pregnant patient. One patient had a T3 level of 540ng/dL 3 hours post-dose, falling to 240ng/dL at 24 hours; supraphysical levels of T3 have also been reported in a case series of 21 patients experiencing nervousness, palpitations and tremor post-dose.(8)

 

      1. When treated with levothyroxine, 17/40 patients had elevated T3 levels (two patients had previously been taking 60mg desiccated thyroid) and 8/40 had raised T4 levels; three of the raised T3 and one of the raised T4 could be accounted for by pregnancy and all of the raised levels occurred in patients taking 200mcg, which may have been too high a dose.

 

        What this study showed is that symptoms of hyperthyroidism may occur following a daily dose of 120-180mg desiccated thyroid. Abnormally high T3 concentrations, measured 2-5 hours post-dose was seen in 90% of patients taking 90mg-180mg desiccated thyroid; while most tolerated this well, six patients had symptoms of hyperthyroidism and benefited from switching to levothyroxine. Raised T3 levels may be hazardous in some patients, especially those with cardiac disease. Changing to levothyroxine resulted in lower T3 and higher T4 levels, resembling those seen in normal subjects.

Retrospective, practice-based review

        The records of 89 patients with hypothyroidism treated with levothyroxine but still symptomatic were compared with those of 832 untreated hypothyroid patients.(16) Forty of the previously treated patients and 278 of the untreated patients were followed-up after treatment with natural desiccated thyroid. The investigators monitored eight main symptoms, (constipation, headache, muscle cramps, depression, Achilles, rheumatoid, cold, fatigue), scored as 0=no symptoms and 2=full-blown symptoms, giving a maximum score of 16.

 

        1. In the levothyroxine-treated patients prior to switching to desiccated thyroid (n=40), the prevalence of symptoms was comparable to with that of the main group of untreated patients, with a mean symptom score was 10.7. The mean 24-hour urine free T3* level was 797.5pmol. The mean levothyroxine dose was 99.7mcg, given for a mean 33.2 months; most patients were taking between 76-100mcg/day.

 

        1. After switching to desiccated thyroid treatment, the mean symptoms score fell from 10.7 to 3.6 and the mean 24-hour urine T3 rose from 767 to 1990pmol. Mean desiccated thyroid dose was 233mg, given for a mean 26.9 months.

 

        1. For the previously untreated patients, the mean symptoms score fell from 10.1 to 3.6 and the 24-hour urine T3 rose from 752 to 1900pmol. The mean desiccated thyroid dose was 300mg, given for a mean 23 months.

 

          The investigators acknowledge that levothyroxine treatment can adequately treat patients with hypothyroidism. They also state that reliance on serum tests (thyroid stimulating hormone and free T4 than on clinical signs and 24-hour urine free T3 may lead to an insufficient dose of thyroid hormone to obtain satisfactory results. But, the investigators did not appear to consider the possibility that the 89 patients still symptomatic on levothyroxine may have simply required a dose increase to control their symptoms, but instead switched them to desiccated thyroid. For all patients, the 24-hour urine free T3 levels were low but were within the reference range. The study is limited by its retrospective nature, lack of control group and lack of titration of levothyroxine to control symptoms.

 

          * A 24-hour urine free T3 measured below the reference range indicates functional hypothyroidism. Free T3 measures the biologically active fraction of total T3, the majority of which is bound by protein carriers and is therefore inactive. The normal range is 592 1850pmol/24 hours.

Limitations

          • This Q&A focuses solely on the use of desiccated thyroid for the treatment of hypothyroidism, not euthyroid hypometabolism.

 

          • This Q&A focuses on evidence that shows clinical effectiveness and safety of armour thyroid compared with that of levothyroxine.

 

          • There may be articles that were not found via the three databases searched (Embase, Medline and AltMedDex). This may be because either the journal is not included in the 3,500+ journals indexed by these databases, or that the article was published prior to 1950 and as such, that practice may be considered obsolete.

References

          (1) The diagnosis and management of primary hypothyroidism. Royal College of Physicians.

http://www.rcplondon.ac.uk/sites/default/files/the-diagnosis-and-management-of-primary-hypothyroidism-revised-statement-14-june-2011_2.pdf

          Accessed 30/12/2013.

 

          (2) Cooper DS. Thyroid hormone treatment: new insights into an old therapy. Journal of the American Medical Association 1989; 261(18):2694-2695.

 

          (3) Armour thyroid (thyroid tablets, USP). Forest Pharmaceuticals, Inc.

http://www.frx.com/pi/armourthyroid_pi.pdf

          Accessed 30/12/2013.

 

          (4) NP Thyroid (thyroid tablets, USP). Acella Pharmaceuticals, LLC.

http://www.npthyroid.com/ACE 15666 PI.pdf

          Accessed 30/12/2013.

 

          (5) Nature-Thyroid (thyroid USP) tablets. RLC Labs

http://www.nature-throid.com/images/Nature-Throid-PI-Rev041121-03.pdf

          Accessed 30/12/2013.

 

          (6) Armour thyroid. Accessed via:

http://www.armourthyroid.com/default.aspx

          on 17/02/14.

 

          (7) Jackson IM, Cobb WE. Why does anyone still use desiccated thyroxine USP? Am J Med 1978; 1978(64):-284.

 

          (8) Lev-Ran A. Part-of-the-day hypertriiodothryoninemia caused by desiccated thyroid. Journal of the American Medical Association 1983; 250(20):2790-2791.

 

          (9) Smith SR. Desiccated thyroid preparations. Obsolete therapy. Arch Intern Med 1984; 144:926-927.

 

          (10) Vaidya B, Pearce SHS. Management of hypothyroidism in adults. Br Med J 2008; 337:284-289.

 

          (11) Hoang TD, Olsen CH, Mai VQ et al. Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J Clin Endocrinol Metab 2013; 98(5):1982-1990.

 

          (12) Sawin CT, Hershman JM, Fernandez-Garcia R et al. A comparison of thyroxine and desiccated thyroid in patients with primary hypothyrodism. Metabolism 1978; 27(10):1518-1525.

 

          (13) Singh SP, Feldman EB, Carter AC. Desiccated thryoid and levothyroxine in hypothyroidism. N Y State J Med 1972; May:1045-1048.

 

          (14) Sturnick MI, Lesses MF. A comparison of the effect of desiccated thyroid and sodium levothyroxine on the serum protein-bound iodine. N Engl J Med 1961; 264(12):608-609.

 

          (15) McGavack TH, Reckendorf HK. Therapeutic activity of desiccated thyroid substance, sodium L-thyroxine and D,L-triiodothyronine. A comparative study. Am J Med 1956; May:774-777.

 

          (16) Baisier WV, Hertoghe J, Eeckhaut W. Thyroid insufficiency. Is thyroxine the only valuable drug? J Nutr Environ Med 1997; 11:159-166.

Quality Assurance

Prepared by

          Alexandra Denby, Regional MI Manager, London Medicines Information Service, Northwick Park Hospital, Harrow.

Date Prepared

          31/12/13

Checked by

          Sheena Vithlani, Principal Medicines Information Pharmacist, London Medicines Information Service, Northwick Park Hospital, Harrow.

Date of check

          January 2014

Contact
nwlh-tr.medinfo@nhs.net

Search strategy

          Internet Search (state search engine; search strategy):

www.google.co.uk

          , armour thyroid desiccated thyroid, natural thyroid

 

        Embase (1980-present), Medline (1950-present) and AltMedDex (1985-present): Date of search: 08/10/2013 via NHS Evidence.

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