Guidelines for the Treatment of Hypothyroidism

Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement – 2014 Dec – free full-text PMC article

related to The Fibromyalgia-Thyroid Connection

Background: A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy

The purpose of this task force was to review

  • the goals of levothyroxine therapy,
  • the optimal prescription of conventional levothyroxine therapy,
  • the sources of dissatisfaction with levothyroxine therapy,
  • the evidence on treatment alternatives, and
  • the relevant knowledge gaps.

This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. 

Methods: Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists

The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation.

Results: We reviewed the following therapeutic categories:

(i) levothyroxine therapy,
(ii) non–levothyroxine-based thyroid hormone therapies,
and
(iii) use of thyroid hormone analogs.

The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones.

We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine–liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes.

We concluded that levothyroxine should remain the standard of care for treating hypothyroidism.

And this is undoubtedly statistically correct. However, Just by virtue of having a chronic illness or chronic pain, we are already not statistically “average”.

Each one of us is an individual consisting of a multitude of interacting individual parts and, because all individual parts are connected and interdependent, it seems we can expect other health parameters to be out of the norm as well.

Levothyroxine (LT4) has been considered the standard of care for treatment of hypothyroidism for many years. This treatment is efficacious when administered orally, has a long serum half-life that permits daily administration, and results in resolution of the signs and symptoms of hypothyroidism in the majority of patients.

However, a small proportion of patients being treated for hypothyroidism feel that LT4 therapy is not efficacious in restoring optimum health.

Several recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking LT4 monotherapy.

For example, much has been learned about the sources and regulation of triiodothyronine (T3) in the plasma and within specific tissues, as well as about the regulation of thyrotropin (TSH). In addition, new data have emerged on dissatisfaction with LT4 therapy being associated with genetic variation in deiodinases, and fatigue and depression in treated hypothyroid patients being linked with genetic variations in thyroid hormone transporters.

In this document the latest data regarding combination therapy, liothyronine (LT3) monotherapy, compounded thyroid hormones, and nutraceuticals are presented.

As a secondary objective, we also review the literature on thyroid hormone analogs.

The potential for genetic variations to influence the ability to optimize thyroid hormone therapy is explored.

The challenges of titrating thyroid hormone therapy in specific groups such as the pediatric, pregnant, and elderly populations are considered.

A recent comprehensive document, the “Clinical Practice Guidelines for Hypothyroidism in Adults Co-sponsored by the American Association of Clinical Endocrinologists (AACE) and the American Thyroid Association (ATA),” covers broader aspects of the management of hypothyroidism (

Section I. Levothyroxine Therapy

■ Recommendation

Levothyroxine is recommended as the preparation of choice for the treatment of hypothyroidism due to its efficacy in resolving the symptoms of hypothyroidism, long-term experience of its benefits, favorable side effect profile, ease of administration, good intestinal absorption, long serum half-life, and low cost.

Thyroid hormone action is an important determinant of development and growth, and in adults plays a critical role in the regulation of the function and metabolism of virtually every organ system

Tissue-specific modulation of the thyroid hormone action is achieved by a complex and redundant control system that includes thyroid hormone secretion, plasma transport, transmembrane transport, activation/inactivation, and interaction with nuclear receptor isoforms and their co-regulators.

Hypothyroid patients are deficient in endogenously produced thyroid hormone.

The rationale for the therapeutic use of LT4 in the treatment of hypothyroidism lies in the peripheral conversion of the exogenously administered pro-hormone thyroxine (T4) into its active metabolite T3

This activating conversion is accomplished by two enzymes, the type 1 (D1) and type 2 (D2) deiodinases. A third deiodinase, type 3 deiodinase (D3) participates in the clearance of both serum T4 and T3

Until the 1970s, the mainstay of thyroid hormone replacement therapy was desiccated thyroid extracts.

Three factors were likely responsible for LT4 becoming the predominant therapy in the latter half of the 20th century:

  • first, the isolation of T4 in 1927 by Kendall;
  • second, the synthesis of T4 and its better-absorbed sodium salt by Chalmers et al.; and
  • third, the demonstration that the biologically active T3 was generated from T4 in humans

Nowhere is mentioned that there were any problems with the desiccated thyroid extracts but they would not have been patentable nor particularly profitable. In fact, it was not until after T4 was synthesized that they demonstrated it converting to T3.

I suspect the impetus to create a synthetic version of the hormone was purely financial because this new molecule could be patented to generate more profit.

Approximately 85 μg of T4 is secreted by the thyroid gland daily.

Of the total daily T3 production of about 33 μg in normal man, approximately 80% (about 26 μg) arises from peripheral conversion from T4, and only about 20% (approximately 6.5 μg) derives from direct thyroidal secretion

It is now well established that while T4 is the major secretory product of the thyroid gland, thyroid hormone action in peripheral tissues is due to the effects of T3 binding to its nuclear receptor, defining T4 as a pro-hormone for T3.

■ Recommendation

Although it may be helpful to follow changes in clinical symptoms longitudinally in patients treated for hypothyroidism, symptoms alone lack sensitivity and specificity and therefore are not recommended for judging adequacy of replacement in the absence of biochemical assessment. Therefore, symptoms should be followed but considered in the context of serum thyrotropin values, relevant comorbidities, and other potential causes.

Choice of Levothyroxine Product

  • Is there a clinical rationale for prescribing brand-name levothyroxine preparations in preference to generic levothyroxine?

■ Recommendation

Prescription of brand name levothyroxine, or alternatively maintenance of the same generic preparation (i.e., maintenance of an identifiable formulation of levothyroxine), is advised.

Switches between levothyroxine products could potentially result in variations in the administered dose and should generally be avoided for that reason (see also recommendation 3d).

  • What medications may alter a patient’s levothyroxine requirement by affecting either metabolism or binding to transport proteins?

■ Recommendation

nitiation or discontinuation of estrogen and androgens should be followed by reassessment of serum thyrotropin at steady state, since such medications may alter the levothyroxine requirement.

Levothyroxine Dosage

  • What factors determine the levothyroxine dose required by a hypothyroid patient for reaching the appropriate serum TSH goal?

■ Recommendation

When deciding on a starting dose of levothyroxine, the patient’s weight, lean body mass, pregnancy status, etiology of hypothyroidism, degree of thyrotropin elevation, age, and general clinical context, including the presence of cardiac disease, should all be considered.

Many factors can affect the LT4 dose required to normalize a particular patient’s TSH

  • What is the best approach to initiating and adjusting levothyroxine therapy?

■ Recommendation

Thyroid hormone therapy should be initiated as an initial full replacement or as partial replacement with gradual increments in the dose titrated upward using serum thyrotropin as the goal. Dose adjustments should be made when there are large changes in body weight, with aging, and with pregnancy, with thyrotropin assessment 4–6 weeks after any dosage change.

  • What are the potential deleterious effects of excessive levothyroxine?

■ Recommendation

The deleterious health effects of iatrogenic thyrotoxicosis include atrial fibrillation and osteoporosis. Because of these effects we recommend avoiding thyroid hormone excess and subnormal serum thyrotropin values, particularly thyrotropin values below 0.1 mIU/L, especially in older persons and postmenopausal women.

  • What are the potential deleterious effects of inadequate levothyroxine?

■ Recommendation

The adverse effects of thyroid hormone deficiency include detrimental effects on the serum lipid profile and progression of cardiovascular disease. We recommend that patients with overt hypothyroidism be treated with doses of levothyroxine that are adequate to normalize serum thyrotropin levels, in order to reduce or eliminate these undesirable effects.

Section II. Therapies Other Than Levothyroxine Alone

Thyroid Extracts

  • In adults requiring thyroid hormone replacement treatment for primary hypothyroidism, is treatment with thyroid extracts superior to treatment with levothyroxine alone?

We recommend that levothyroxine be considered as routine care for patients with primary hypothyroidism, in preference to use of thyroid extracts.

Although there is preliminary evidence from a short-duration study that some patients may prefer treatment using thyroid extracts, high-quality controlled long-term outcome data are lacking to document superiority of this treatment compared to levothyroxine therapy. Furthermore, there are potential safety concerns related to the use of thyroid extracts, such as the presence of supraphysiologic serum triiodothyronine levels and a paucity of long-term safety outcome data.

So, the fact that patients prefer treatment with thyroid extracts is overruled (not contradicted) by a lack of scientific evidence.

This does not seem like the right way to practice medicine. Are we treating the numbers or the person?

Desiccated thyroid or thyroid extract refers to preparations that are derived from the thyroid gland of animals. These preparations were the primary therapy for hypothyroidism until the advent of synthetic T4 preparations in the 1960s.

All commercially available prescription desiccated preparations are derived from pigs. As per the United States Pharmacopeia (USP), desiccated thyroid is “the cleaned, dried, and powdered thyroid gland previously deprived of connective tissue and fat. It is obtained from domesticated animals that are used for food by humans.”

Tablets are measured for T4 and T3 content and are formulated into doses expressed as “grains” with 1 grain (65 mg) tablets containing 38 μg of T4; 9 μg of T3; protein-bound iodine; and unmeasured quantities of diiodothyronine, monoiodothyronine, and calcitonin, to which inactive ingredients are added for tablet stability.

One process used to achieve specific dosage strengths is to mix different batches of the product during manufacture. The bioavailability of the T4 and T3 components has been shown to be the same between desiccated thyroid and synthetic preparations

There are two main clinical concerns with the use of desiccated thyroid preparations, both of which center on their T3 component.

The ratio of T4 to T3 in desiccated thyroid preparations is 4.2:1, which is significantly lower than the 14:1 ratio of secretion by the human thyroid gland.

This relative excess of T3 leads to supraphysiologic levels of T3. In addition, due to the shorter half-life of T3, fluctuations of T3 occur over the course of the day, with peak levels shortly after dosing 

But since our body’s conversion of T4 to T3 is ruled by our own body’s determined ratio, such excess would be compensated for by less conversion of T4.

There are no published controlled long-term outcome trials of the use of desiccated thyroid extract. Furthermore, data from studies of combinations of LT4 and LT3 therapy do not suggest additional benefit from the addition of LT3 to LT4 replacement therapy

Synthetic Combination Therapy and the Rationale for Its Use

  • Do genetic variants in thyroid hormone pathway genes (deiodinases or thyroid hormone transporters) affect the serum or tissue levels of thyroid hormones in healthy euthyroid individuals (state of having normal thyroid gland function) or hypothyroid patients taking replacement therapy?

■ Summary statement

Specific polymorphisms in the deiodinases are consistently associated with very small changes in serum thyroid hormone levels.

Insufficient data exist to draw any conclusion about the clinically relevant effects of deiodinase or transporter polymorphisms on tissue thyroid hormone levels.

  • In adults requiring thyroid hormone replacement treatment for primary hypothyroidism who feel unwell while taking levothyroxine, is combination treatment including levothyroxine and liothyronine superior to the use of levothyroxine alone?

■ Recommendation

For patients with primary hypothyroidism who feel unwell on levothyroxine therapy alone (in the absence of an allergy to levothyroxine constituents or an abnormal serum thyrotopin), there is currently insufficient evidence to support the routine use of a trial of a combination of levothyroxine and liothyronine therapy outside a formal clinical trial or N-of-1 trial, due to uncertainty in long-term risk benefit ratio of the treatment and uncertainty as to the optimal definition of a successful trial to guide clinical decision-making.

This sounds like unnecessarily complicated and convoluted reasoning against combination therapy. The uncertainties mentioned apply equally to any thyroid therapy, but are only considered deal-breakers when evaluating combination therapy.

Again, are we treating the numbers or the person?

The main problem seems to be whether the purpose of therapy is to reach certain statistically validated numerical values (T4, T3, TSH levels) or to make people feel well (less sick).

Additional research targeting those with relatively low serum triiodothyronine concentrations, but normal thyrotropin levels during monotherapy is needed to address whether there is a subgroup of patients who might benefit from combination therapy.

Triiodothyronine Monotherapy for Hypothyroidism

  • Are there data regarding therapy with triiodothyronine alone, either as standard liothyronine or as sustained release triiodothyronine, that support the use of triiodothyronine therapy alone for the treatment of hypothyroidism?

■ Recommendation

Although short-term outcome data in hypothyroid patients suggest that thrice-daily synthetic liothyronine may be associated with beneficial effects on parameters such as weight and lipids, longer-term controlled clinical trials using a longer-acting form of triiodothyronine are needed before considering the endorsement of synthetic liothyronine therapy for routine clinical use.

Compounded Thyroid Hormones

  • What is the recommendation regarding therapy with compounded thyroid hormones (either levothyroxine or liothyronine) for treatment of hypothyroidism based on current evidence?

■ Recommendation

We recommend against the routine use of compounded thyroid hormones due to concerns about safety and potency and due to the lack of data proving superiority to standard thyroid hormone preparations.

However, in the case of suspected allergy to an excipient of standard thyroid hormone preparations that cannot be avoided with a change in brand or dose formulation, including a trial of levothyroxine gel capsules, it may be reasonable to consider use of compounded products, although a controlled study of this approach has not been published.

Nutraceuticals

  • Is there a role for the use of dietary supplementation, nutraceuticals, and over-the-counter products in either hypothyroid or euthyroid individuals?

■ Recommendation

We recommend against the use of dietary supplements, nutraceuticals, or other over-the-counter products either in euthyroid individuals or as a means of treating hypothyroidism.

We particularly caution against the use of pharmacologic doses of iodine because of the risk of thyrotoxicosis and hypothyroidism in those with intact thyroid glands susceptible to becoming further dysregulated because of underlying thyroid pathology.

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