LEVOTHYROXINE THERAPY

• 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. ( S-M)
• Levothyroxine replacement therapy has three main goals. These are:
• To provide resolution of the patients’ symptoms and hypothyroid signs, including biological and physiologic markers of hypothyroidism
• To achieve normalization of serum TSH with improvement in thyroid hormone concentrations
• To avoid overtreatment (iatrogenic thyrotoxicosis), especially in the elderly. (S-M)

• 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 TSH values, relevant comorbidities, and other potential causes. (W-L)
• Tissue biomarkers of thyroid hormone action are not recommended for routine clinical use, outside of the research setting, since these parameters are not sensitive, specific, readily available, or standardized. (W-L)
• Prescription of brand name levothyroxine, or alternatively maintenance of the same generic preparation (i.e., maintenance of an identifiable formulation of levothyroxine [See Table 1]), is advised.
• General populations (W-L)
• Frail patients, high-risk thyroid cancer patients, pregnant patients (S-L)
• Early childhood hypothyroidism (S-M)

Note: Switches between levothyroxine products could potentially result in variations in the administered dose and should generally be avoided for that reason.

• Because use of different levothyroxine products may sometimes be associated with altered serum TSH values, a change in an identifiable formulation of levothyroxine (brand name or generic [See Table 1]) should be followed by re-evaluation of serum TSH at steady state. (W-L)
• Although there are preliminary small studies suggesting that levothyroxine dissolved in glycerin and supplied in gelatin capsules may be better absorbed than standard levothyroxine in selected circumstances such as concomitant use of proton pump inhibitors or concomitant coffee consumption, the present lack of controlled long-term outcome studies does not support a recommendation for the use of such preparations in these circumstances. (W-L)

Note: Switch to a gel capsule might be considered in the rare case of putative allergies to excipients.

• Because co-administration of food and levothyroxine is likely to impair levothyroxine absorption, the ATA recommends that, if possible, levothyroxine be consistently taken either 60 minutes before breakfast or at bedtime (3 or more hours after the evening meal) for optimal, consistent absorption. (W-M)
• The ATA recommends that, where feasible, levothyroxine should be separated from other potentially interfering medications and supplements (e.g., calcium carbonate and ferrous sulfate [See Table 2]). A 4-hour separation is traditional but untested. (W-L)

Note: Other medications (e.g., aluminum hydroxide and sucralfate) may have similar effects but have been insufficiently studied.

• In patients in whom levothyroxine dose requirements are much higher than expected, evaluation for gastrointestinal disorders such as Helicobacter pylori–related gastritis, atrophic gastritis, or celiac disease should be considered. Furthermore, if such disorders are detected and effectively treated, re-evaluation of thyroid function and levothyroxine dosage is recommended. (S-M)
• Initiation or discontinuation of estrogen and androgens should be followed by reassessment of serum TSH at steady state since such medications may alter the levothyroxine requirement. Serum TSH should also be reassessed in patients who are started on agents such as tyrosine kinase inhibitors that affect thyroxine metabolism and thyroxine or triiodothyronine deiodination (See Table 2). (S-L).

Note: Serum TSH monitoring is also advisable when medications such as phenobarbital, phenytoin, carbamazepine, rifampin, and sertraline are started.

• When deciding on a starting dose of levothyroxine, the patient’s weight, lean body mass, pregnancy status, etiology of hypothyroidism, degree of TSH elevation, age, and general clinical context, including the presence of cardiac disease, should all be considered. In addition, the serum TSH goal appropriate for the clinical situation should also be considered. (S-M)
• 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 TSH as the goal. Dose adjustments should be made when there are large changes in body weight, with aging, and with pregnancy, with TSH assessment 4-6 weeks after any dosage change. (S-M)
• The deleterious health effects of iatrogenic thyrotoxicosis include atrial fibrillation and osteoporosis. Because of these effects, the ATA recommends avoiding thyroid hormone excess and subnormal serum TSH values, particularly TSH values below 0.1 mIU/L, especially in older persons and postmenopausal women. (S-M)
• The adverse effects of thyroid hormone deficiency include detrimental effects on the serum lipid profile and progression of cardiovascular disease. The ATA recommends that patients with overt hypothyroidism be treated with doses of levothyroxine that are adequate to normalize serum TSH levels, in order to reduce or eliminate these undesirable effects. (S-M)
• Perceived allergy or intolerance to levothyroxine can be managed by changing the dose or product, including consideration of gel capsules, and possibly by treating concomitant iron-deficiency anemia. In selected cases, a consultation with an allergist may be appropriate. (W-L)
• The ATA recommends considering patients’ underlying medical conditions (such as atherosclerotic heart disease) in order to establish realistic treatment goals and avoid exacerbation of underlying comorbidities. (W-L)
• The treatment goals of hypothyroidism are the same for patients with psychosocial, behavioral, and mental health conditions as for the general population. However, referral to a mental health professional should be considered if the severity of the symptoms is not sufficiently explained by the severity of the biochemically confirmed thyroid dysfunction or another medical condition, or if the mental health condition is impairing effective management of levothyroxine replacement therapy. (S-L).
• In older patients, levothyroxine should generally be initiated with low doses, and the dose titrated slowly based on serum TSH measurements. It should be recognized that normal serum TSH ranges are higher in older populations (such as those >65 years) and that higher serum TSH targets may be appropriate. (S-M)
• If prescription of daily levothyroxine is not successful in maintaining a normal serum TSH, weekly oral administration of the full week’s dose of levothyroxine should be considered in individuals in whom adherence cannot otherwise be sustained. (W-L)
• There is insufficient evidence of benefit to recommend that treatment with levothyroxine be targeted to achieve low-normal TSH values or high-normal triiodothyronine values in patients with hypothyroidism who are overweight, those who have depression or dyslipidemia, or those who are athyreotic. (S-M)
• Of the established instruments used to measure hypothyroid symptoms, data are lacking regarding their sensitivity and specificity in the ‘‘everyday’’ clinical setting to recommend their routine clinical use. (S-M)

Note: Further studies are needed to determine if and how to combine general psychological screening instruments, hypothyroidism-specific tools, and laboratory assessment of thyroid function to measure the impact of levothyroxine replacement therapy on psychological well-being, treatment satisfaction, and preference in clinical practice.

• A minority of patients with hypothyroidism, but normal serum TSH values, may perceive a suboptimal health status of unclear etiology. Acknowledgment of the patients’ symptoms and evaluation for alternative causes is recommended in such cases. (W-L)

Note: Future research into whether there are specific subgroups of the population being treated for hypothyroidism who might benefit from combination therapy should be encouraged.

Hypothyroidism in Pregnant Women, Infants, and Children

• Pregnant women with overt hypothyroidism should receive levothyroxine replacement therapy with the dose titrated to achieve a TSH concentration within the trimester-specific reference range. Serial serum TSH levels should be assessed every 4 weeks during the first half of pregnancy in order to adjust levothyroxine dosing to maintain TSH within the trimester-specific range. Serum TSH should also be reassessed during the second half of pregnancy. For women already taking levothyroxine, two additional doses per week of the current levothyroxine dose, given as one extra dose twice weekly with several days separation, may be started as soon as pregnancy is confirmed. (S-M)
• In infants, levothyroxine replacement at a dose of 10-15 μg/kg/d should be initiated once newborn screening is positive, pending the results of confirmatory testing. Higher doses may be required for infants with severe congenital hypothyroidism. (S-H)

Note: The aim of therapy is to maintain the serum thyroxine in the mid- to upper half of the pediatric reference range and the serum TSH in the mid- to lower half of the pediatric reference range. The target should be to normalize serum thyroxine approximately 2-4 weeks after initiation of therapy. Once the proper dose is identified, surveillance testing with a serum TSH and thyroxine should be performed every 1-2 months during the first year of life with decreasing frequency as the child ages.

• All children with overt hypothyroidism should receive levothyroxine replacement therapy to normalize their biochemical parameters and reverse their signs and symptoms of hypothyroidism. (S-H)
• Due to the low risks of levothyroxine replacement therapy in children with subclinical hypothyroidism, many clinicians still consider it reasonable to initiate treatment to avoid any potential risk of negative impact on growth and development. Treatment is generally not recommended when the TSH is 5-10 mIU/L. For patients with subclinical hypothyroidism and TSH >10 mIU/L with signs and symptoms consistent with primary thyroid disease and/or risk factors associated with progression, levothyroxine replacement may be reasonable. (W-L)

Secondary Hypothyroidism

• In patients with secondary hypothyroidism, the primary biochemical treatment goal should be to maintain the serum free thyroxine values in the upper half of the reference range. However, the serum free thyroxine target level may be reduced in older patients or patients with comorbidities, who may be at higher risk of complications from thyroid hormone excess. (S-M)
• Although it may be helpful to follow changes in clinical parameters in patients treated for secondary hypothyroidism, such parameters alone lack sensitivity and specificity. There is a limited amount of evidence suggesting that clinical parameters are helpful as a secondary means of judging adequacy of replacement with levothyroxine in patients with secondary hypothyroidism in whom biochemical assessment is limited to serum free thyroxine levels. (W-M)
• In patients with secondary hypothyroidism in whom the only available biochemical thyroid parameters are thyroid hormone levels, tissue markers of thyroid hormone action may be used, in addition to thyroid hormone parameters, as an adjunctive means of judging the adequacy of levothyroxine replacement. (W-L)

Levothyroxine in Euthyroid Individuals

• The ATA strongly recommends against the use of levothyroxine treatment in patients who have nonspecific symptoms and normal biochemical indices of thyroid function because no role exists for use of levothyroxine in this situation. (S-H)
• The ATA recommends against the routine use of levothyroxine for the treatment of euthyroid individuals with depression due to a paucity of controlled data examining treatment efficacy in this setting. (W-L)
• The ATA recommends against the treatment of obesity with levothyroxine in euthyroid individuals due to a lack of treatment efficacy for this condition (S-M)
• The ATA recommends against the treatment of urticaria with levothyroxine in euthyroid individuals due to a lack of treatment efficacy for this condition. (S-M)
• Factitious thyrotoxicosis should be treated with discontinuation of the exogenous thyroid hormone with education and/or psychiatric consultation as appropriate. (S-L).

THERAPIES OTHER THAN LEVOTHYROXINE ALONE

• The ATA recommends that levothyroxine be considered as routine care for patients with primary hypothyroidism, in preference to use of thyroid extracts. (S-M)

Note: 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.

• There is no consistently strong evidence of superiority of combination therapy over monotherapy with levothyroxine. Therefore, the ATA recommends against the routine use of combination treatment with levothyroxine and liothyronine as a form of thyroid replacement therapy in patients with primary hypothyroidism, based on conflicting results of benefits from randomized controlled trials comparing this therapy to levothyroxine therapy alone and a paucity of long-term outcome data (See Table 3). (W-M).
• 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 TSH), 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. (I)
• Currently, genetic testing is not recommended as a guide to selecting therapy for three reasons:
• Although there are data suggesting that specific polymorphisms of the type 2 deiodinase gene might be associated with therapeutic response to combination synthetic levothyroxine and liothyronine therapy, controlled confirmatory studies are needed.
• Currently genetic testing for these specific deiodinase polymorphisms is only available in the research setting.
• 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. (S-M)
• 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. (S-M)
• Although some uncontrolled and nonrandomized data exist concerning successful use of liothyronine in euthyroid patients with depression, larger, prospective randomized placebo-controlled studies are needed to more completely define the potential role of liothyronine in this condition, balancing the risks and benefits of therapy to measurable clinical outcomes. (W-L)
• The ATA recommends against the use of synthetic liothyronine therapy in treating euthyroid patients with obesity, due to a lack of controlled data proving treatment efficacy for this indication. (S-L).
• The ATA recommends 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. (S-L)

Note: 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.

• The ATA recommends 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. (S-L).

Wilson’s Syndrome

• There are no credible scientific data to support the existence of “Wilson’s syndrome.” The ATA recommends against the use of triiodothyronine escalation therapy for this indication due to a lack of proven treatment benefit and safety concerns relating to the risk of thyrotoxicosis. (S-L).

HOSPITALIZED PATIENTS

• In hospitalized, non-critically ill patients with a pre-established diagnosis of hypothyroidism who are found to have an elevated TSH measurement, consideration should be given to institution or adjustment of levothyroxine replacement. (S-L).

Note: Factors such as the degree of clinical and biochemical hypothyroidism, active comorbidities, and details of administration of levothyroxine (e.g., dosage, timing, and other factors impacting absorption) are relevant considerations in this situation.

• The therapeutic goal of levothyroxine replacement in noncritically ill patients is long-term normalization of serum TSH when steady-state thyroid hormone levels are achieved. (S-L)

Note: The ATA does not recommend titrating the levothyroxine dose to serum free thyroxine levels unless serum TSH cannot be relied upon (e.g., following pituitary surgery).

• For hospitalized but not critically ill patients, oral levothyroxine treatment is recommended. If this is not feasible, other enteral routes can be used. However, if there are concerns about significant malabsorption or there are other clinical reasons why a patient cannot be given enteral levothyroxine, intravenous levothyroxine may be administered until enteral absorption improves. (W-L)

Note: If using intravenous levothyroxine, the equivalent intravenous dose is approximately 75%, assuming the enteral levothyroxine dose had achieved euthyroidism.

• For hospitalized but not critically ill patients who are about to be treated with levothyroxine, the possibility of adrenal insufficiency should be considered. If there is sufficient clinical or biochemical evidence to consider this diagnosis, adrenal insufficiency should be ruled out, or empiric treatment should be provided. (S-L).
• The ATA recommends against the routine use of liothyronine as a form of therapy for hospitalized patients with heart failure and low serum triiodothyronine concentrations given the mixed data from short-term trials, the hypothetical risks, and pending further randomized trials confirming benefit and safety. (W-M).

Myxedema Coma

• Initial thyroid hormone replacement for myxedema coma should be levothyroxine given intravenously. (S-L).

Note: A loading dose of 200-400 μg of levothyroxine may be given, with lower doses given for smaller or older patients and those with a history of coronary disease or arrhythmia. A daily replacement dose of 1.6 μg/kg body weight, reduced to 75% as long as it is being intravenously administered, can be given thereafter. Oral therapy, or other enteral therapy if the oral route cannot be employed, may be instituted after the patient improves clinically.

• Empiric glucocorticoid coverage should be employed as part of the initial therapy for myxedema coma, with intravenous glucocorticoid administration, at doses appropriate for the stressed state, preceding levothyroxine administration. (S-L).
• Given the possibility that thyroxine conversion to triiodothyronine may be decreased in patients with myxedema coma, intravenous liothyronine may be given in addition to levothyroxine. High doses should be avoided given the association of high serum triiodothyronine during treatment with mortality. (W-L)

Note: A loading dose of 5-20 μg can be given, followed by a maintenance dose of 2.5-10 μg every 8 hours, with lower doses chosen for smaller or older patients and those with a history of coronary artery disease or arrhythmia. Therapy can continue until the patient is clearly recovering (e.g., until the patient regains consciousness and clinical parameters have improved).

• Intravenous levothyroxine treatment in severely hypothyroid patients may lead to improvement in cardiovascular, renal, pulmonary, and metabolic parameters within a week. (W-L)

Note: Serum thyroxine and triiodothyronine concentrations may improve or normalize with a similar time frame, with more gradual improvement in serum TSH. Thus, the therapeutic endpoints in myxedema coma should be improved mental status, improved cardiac function, and improved pulmonary function. Measurement of thyroid hormones every 1-2 days is reasonable to ensure a favorable trajectory in the biochemical parameters. While optimal levels for serum TSH and thyroid hormones are not well defined in this circumstance, failure of TSH to trend down or for thyroid hormone levels to improve could be considered indications to increase levothyroxine therapy and/or add liothyronine therapy, whereas high serum triiodothyronine could be considered an indication to decrease therapy given safety concerns.

• The ATA recommends against the use of levothyroxine as a form of therapy for hospitalized patients experiencing critical illness exhibiting the nonthyroidal illness syndrome. (S-M)

Note: The few randomized controlled trials comparing levothyroxine therapy to no treatment have not shown significant clinical benefit and have raised safety concerns that limit support for this approach.

• The ATA recommends against the use of liothyronine as a form of therapy for hospitalized patients experiencing critical illness exhibiting the nonthyroidal illness syndrome. (W-M).

Note: Although low doses of liothyronine have not been linked to harm in clinical trials, data showing any significant clinical benefit are also lacking.

USE OF THYROID HORMONE ANALOGS

• Although preclinical data suggest that the concept of thyromimetic use for treatment of non-hypothyroid-related medical conditions may be promising, the ATA recommends against the use of such drugs outside of the research setting due to concerns about the lack of clear benefit or excessive side effects of currently available preparations. (S-L)
• The therapeutic goals of the treatment of patients with genetic syndromes of resistance to thyroid hormone are to improve the symptoms caused by excessive TRα signaling while minimizing the symptoms caused by deficient TRβ signaling. (W-L)
• Although preliminary data from small case series suggest that the use of TRIAC in patients with genetic syndromes of resistance to thyroid hormone may be promising, more clinical research is needed before the use of thyroid hormone analogs can be recommended for this indication. (W-L)

ETHICS FRAMEWORK

• Clinical ethical principles in levothyroxine treatment for hypothyroidism revolve around two core ethical principles in medicine: the Principles of Beneficence and Non- Maleficence, which guide the risk/benefit analysis in clinical practice and protect clinicians from deviating from practice to satisfy inappropriate patient demands. Additional ethical obligations revolve around the professional virtues of competence and intellectual honesty.
• There should be recognition that there are not enough data to resolve clinical disagreement among thyroid experts (called ‘‘clinical equipoise’’) regarding treatment for hypothyroidism. Clinical equipoise is disturbed only by the results of well-designed randomized controlled trials that have the statistical power to settle the question of efficacy between monotherapy and combination therapy, or other forms of therapy.

Table 1. Thyroid Hormone Preparations

Table 2. Medications Potentially Affecting Levothyroxine Dose Requirement

Table 3. Potential Concerns About Long-Term Combination Therapy Use in the General Population With Hypothyroidism