Are We Restoring Thyroid Hormone Signaling in LT4-Treated Patients with Residual Symptoms of Hypothyroidism?

Abstract

Levothyroxine (LT4) at doses that maintain serum thyrotropin (TSH) levels within the normal range constitutes the standard of care for the treatment of hypothyroidism. After a few months, this eliminates signs and symptoms of overt hypothyroidism in the majority of patients, thanks to the endogenous activation of thyroxine (T4) to triiodothyronine (T3), the biologically active thyroid hormone. Still, a small percentage of the patients (10–20%) exhibit residual symptoms, despite having normal serum TSH levels. These symptoms include cognitive, mood, and metabolic deficits, with a significant impairment in psychological well-being and quality of life. In these patients, the coexistence of a non-thyroid condition should be investigated and treated. However, despite that, residual symptoms often persist. It is not entirely clear what makes some patients more susceptible, but it could be a relative deficiency of T3, hence the justification for combination therapy with LT4+liothyronine (LT3). A score of clinical trials comparing therapy with LT4 versus LT4+LT3 concluded that both are safe and equally effective (neither is superior), but these trials failed to recruit a sufficiently large number of patients with residual symptoms. New clinical trials that considered LT4-treated symptomatic patients revealed that such patients benefit from and prefer therapy containing LT4+LT3; desiccated thyroid extract (DTE) has also been used with similar results. A recent joint statement of the American, British, and European Thyroid Associations recommends that a trial with combination therapy be offered to patients with hypothyroidism that do not fully benefit from therapy with LT4. Here we present a critical review of these findings and offer a practical approach to initiate patients on combination therapy with LT4+LT3.

Introduction

Hypothyroidism is a condition that occurs as a result of insufficient production of thyroid hormones (TH) (1). The thyroid gland produces about 100 mcg of thyroxine (T4) per day in a healthy adult. However, the active thyroid hormone is 3,3’,5-triiodothyronine (T3), ~20 % of which is secreted directly from the thyroid gland (around 5 mcg/day in healthy adults), while the rest (around 25 mcg) comes from extrathyroidal outer ring deiodination of thyroxine (T4) (2).

Chronic autoimmune thyroiditis is the most common cause of hypothyroidism in iodine-sufficient areas. The reduction in TH levels seen in patients with hypothyroidism leads to insufficient TH signaling (and the subsequent modification in the expression of TH-responsive genes) in multiple body systems (3, 4). For example, T3 universally accelerates metabolic reactions, which leads to a faster rate of energy expenditure and heat production. Thus, when T3 levels are low, the expression of the genes involved in these pathways is reduced, slowing down the overall metabolic rate and explaining typical signs and symptoms of hypothyroidism, namely fatigue, hypometabolism, weight gain, cold intolerance. Although T3 also regulates gene expression in the brain (and hypothyroidism is associated with major alterations in mood and cognitive function), the cellular pathways involved in the central nervous system are less clear. Nonetheless, hypothyroidism can be a debilitating disease and, if left untreated, it may lead to what is known as myxedema coma (fortunately this is rarely seen).

Patients with overt hypothyroidism may present with few or no symptoms at all, while others have clearcut identifiable symptoms and/or signs of TH deficiency. Nonetheless, all exhibit an elevation of thyroid stimulating hormone (TSH) levels and a reduction in T4 levels in the circulation. A recent analysis of a large administrative claims dataset from 2012–2019, and the 2009–2010 and 2011–2012 National Health and Nutrition Examination Survey (NHANES) cycles estimated that approximately 8.2 % of the United States population exhibits overt hypothyroidism (5). At the same time, patients may exhibit subclinical hypothyroidism, a condition characterized by an elevated plasma TSH (<10 mU/L) in an other-wise asymptomatic (or minimally symptomatic) patient with normal FT4 levels. It is estimated that the prevalence of both overt and subclinical hypothyroidism has increased over time and has reached 11.7% of the adult population (5).

The ideal treatment of hypothyroidism should restore circulating levels of TH and normalize their biological effects throughout the body. Therapy with desiccated thyroid extract (DTE) contains both T4 and T3 (4:1). It was developed in the 1890s and remained the standard of care during the better part of the 20^th century (6). Since the early 1960s, therapy with synthetic LT4+LT3 has also been used in the United Kingdom (7) and the United States (8), and therapy with DTE was all but abandoned with the discovery that T4 is endogenously activated to T3 via the deiodinases (9). Even though there were signs that some patients preferred and benefited from therapy with DTE or LT4+LT3 (10), clinical guidelines favored therapy with LT4 given the safety concerns with LT3 (the fast T3 kinetics in the plasma results in a peak and a trough that may cause palpitations and fine tremor in those patients taking a relatively large dose of LT3) and reports of potency inconsistency among brands and lots of the same brand (11).

The current standard of care for the treatment of patients with hypothyroidism is daily levothyroxine (LT4) tablets at doses that normalize TSH levels (11, 12). It is expected (and generally assumed) that normalization of TSH levels occurs alongside the resolution of symptoms of hypothyroidism. And indeed, this is the case after a few months of treatment for the majority of patients. Nonetheless, a consensus exists today that a poorly defined minority of LT4-treated patients exhibit persistent symptoms that are thyroid-related despite normalization of the serum TSH (13). It is difficult to ascertain the exact number because it will depend on the intrinsic nature of the population served by each practice, e.g. endocrinologists vs. general internists. Two seminal studies indicate that this number varies between 10–20% of all LT4-treated patients (14, 15).

We have known that treatment with LT4 does not always resolve all symptoms of hypothyroidism since the early 1970s (16) and that some patients resisted being switched off DTE (6). Others wrote letters alerting providers of how they felt (17), which led to the development of thyroid-specific QoL questionnaires (14) that later were expanded and validated in different languages (18). While LT4 is safe and resolves signs and symptoms of overt hypothyroidism, a seminal community-based study revealed that patients treated with LT4, even with a normal serum TSH, exhibited a significant impairment in psychological well-being compared to controls matched for age, sex, and comorbidities (14). In another study in which cognitive functioning tests were applied, LT4-treated patients showed poor performance in various domains, especially on complex attention tasks and verbal memory tests (14). Quality of life was also decreased in these patients as compared with those of the general population, independently of serum TSH levels (16). Similar results were obtained in other centers (19, 20), except for the Rancho Bernardo study (21), in which differences may have been masked by the natural cognitive decline exhibited by the much older population in that cohort (both LT4-treated and control populations included individuals up to 94 years old). Sometimes referred to as brain fog, these cognitive-, mood-, and QoL-residual symptoms include mental fatigue, memory, and sleep problems, difficulty focusing and making decisions, anxiety, and mental confusion, which may be present during most of the day (22).

Textual-data analysis of an open-ended survey of thousands of patients self-referred as having hypothyroidism and brain fog identified two major groups of responses, namely symptom-centric (issues with language/memory and sleep/time) and medical-centric (issues with disease/diagnosis, patient/doctor, and medication) (22). As in other surveys (23), concerns with the patient/doctor relationship came across very clearly. The textual analysis indicated that many patients have the perception that physicians do not regard their residual symptoms as thyroid-related and/or within their sphere of responsibility, logically leading to frustration and a feeling of neglect.

Adequately treated patients with hypothyroidism may also exhibit abnormal metabolic signs or symptoms, including difficulty managing body weight (23) (they weigh approximately 10 pounds more than a control-matched population (24)), and lower basal metabolic rate (BMR) (25–28). One should keep in mind, however, that hypothyroidism is rarely an isolated cause of obesity, given that even in the control-matched population, the BMI was above normal but within the overweight range (43). Furthermore, LT4-treated patients may also have slightly elevated serum cholesterol levels (29–31) despite being more likely to be on statin medications (24, 32). While these parameters have been studied in relatively smaller cohorts and mostly in cross-sectional studies, the results are consistent and indicate that metabolic parameters should be incorporated into the main outcomes of future clinical trials investigating TH treatments.

The purpose of this article is to review the relevant evidence indicating the incomplete effectiveness of treatment with LT4, along with potential factors that may explain such persistent symptoms. We advocate that, once thyroid-independent factors have been ruled out, an alternative treatment approach should be used for the subset of patients that remain symptomatic on LT4. The recognition of these two points (and the appropriate corrective actions) should improve the overall quality of treatment provided to patients with hypothyroidism. It should also assist physicians, particularly general endocrinologists, in the discussion of definitive treatment of thyroid diseases and in setting appropriate therapeutic expectations with their patients.

Does treatment of hypothyroid patients with LT4 normalize TH economy?

The residual symptoms experienced by LT4-treated patients are similar to those symptoms experienced by patients with overt hypothyroidism, albeit less intense (33). This suggests that treatment with LT4 might not normalize TH signaling in all tissues. It is logical to conceive a scenario in which, once a non-thyroid-related condition has been ruled out (or adequately treated), residual symptoms result from the incomplete recovery of T3 signaling in specific organs, despite the normalization of serum TSH. Most symptoms identified so far are cognitive and mood-related, hence normalization of TH signaling in the brain seems to be particularly problematic in these patients (34).

Iodine deficiency has been the major driving force that shaped how the hypothalamus-pituitary-thyroid (HPT) system evolved. In adult individuals with mild-moderate iodine deficiency, T4 secretion decreases, and TSH secretion is accelerated, increasing the T3/T4 ratio in thyroid secretion. The drop in serum T4 also accelerates T4 to T3 conversion via the type 2 deiodinase (D2) in multiple tissues. As a result of these homeostatic adjustments, serum T3 levels remain unaffected in adult individuals living in areas of mild-moderate iodine deficiency. Studies of mice carrying inactive genes for the deiodinases revealed that also in this case the HPT adjusts to preserve serum T3 levels, despite tolerating higher serum T4 and TSH levels (35, 36). Thus, it is tempting to conclude that the prime directive of the HPT axis is to adjust the T3/T4 ratio in thyroid secretion (via TSH secretion) to defend the normalcy of serum T3 levels. Patients with hypothyroidism lack such an adaptive mechanism, which begs the question of whether the deiodinases alone can preserve serum T3 levels without the contribution of the thyroid gland (3, 36). This is important because T3 is the biologically active TH. Its levels in the circulation are in equilibrium with and reflect the T3 content in most tissues (except for those tissues that express D2 such as the brain and pituitary gland) (34).

Rightly so, not a lot of focus has been placed on T3 levels in the diagnosis of patients with hypothyroidism. Because the HPT’s directive is to preserve circulating T3 levels, these are highly regulated and thus have poor diagnostic value. In a patient with autoimmune thyroiditis, an increase in serum TSH and a drop in FT4 are the early signs of a thyroid failure, and both contribute with T3 homeostasis (TSH accelerates the relative secretion of T3 and the low T4 levels accelerate the D2-mediated T4 to T3 conversion). Therefore, the changes in TSH and T4 are followed by a distant drop in serum T3 levels (37).

Unfortunately, a similar rationale was used to justify not monitoring T3 levels in the follow-up of LT4-treated patients (not common in clinical practice or recommended in clinical guidelines). But this rationale ignores that the prime directive of the HPT axis is to preserve circulating T3 levels, despite abnormal TSH and T4 levels. We interpret this as a strong indication that we should have the same goal while treating patients with hypothyroidism, i.e. restoring and preserving circulating T3 levels.

Unfortunately, this has not been highlighted in clinical guidelines, despite the early observation that LT4-treated patients (with normal serum TSH levels) maintain slightly lower serum T3 levels (38). Whereas some studies might not have been sufficiently powered to reproduce these findings, the majority of the studies performed since the 1970s indicate that LT4-treated patients have relatively lower serum T3 and relatively higher serum T4 levels; approximately 15% of the patients have serum T3 levels below the normal reference range (6). While the available data does not allow us to conclude that the residual symptoms experienced by some of the LT4-treated patients are connected with the incomplete normalization of serum T3 levels, the evidence is very suggestive and deserves further investigation.

What could explain the relatively low T3 levels in LT4-treated patients? We know that the rate at which T4 is converted to T3 (in the tissues that provide T3 for the circulation) correlates inversely with the levels of T4. Thus, at the beginning of the treatment of hypothyroidism T4 is rapidly converted to T3, building up substantial amounts of T3 in the circulation, even before serum T4 levels have been normalized. However, further increases in serum T4 do not result in proportional increases in serum T3 levels (39). This is likely due to the downregulation of the T3 production via D2. T3 levels will only increase substantially once FT4 is above the normal reference range, at which point the participation of the D1 pathway becomes relatively more significant (39). Notably, this homeostatic mechanism (i.e. the drop in D2 activity in response to T4), does not occur in the hypothalamus-pituitary unit, where T4 continues to be converted to T3 at high rates despite an elevation in serum T4 levels (40). As a consequence, during treatment with LT4, T3 levels are rapidly restored in the hypothalamus-pituitary unit, normalizing serum TSH levels, even as the serum T3 levels remain relatively lower. A common DIO2 polymorphism reduces the D2 activity by about 20% (41, 42) and has been used to explain the relatively lower serum T3 levels in LT4-treated patients that are carriers of the polymorphism (43), but these latter findings have not been universally reproduced (44). Rare loss of function D1 mutations have also been described (45), but the extent to which they could disrupt TH homeostasis in LT4-treated patients remains unknown.

Residual thyroid tissue participates in the T3 economy during therapy with LT4

The observation that the HPT system plays a critical role in maintaining serum T3 levels and that this homeostatic mechanism is lost in patients with hypothyroidism (36), raises the question as to whether any residual thyroid tissue may play a role, even if less significant. This of course could be important when planning definitive treatment for thyroid disease such as total vs. partial thyroidectomy. To address that question, roughly 400 consecutive LT4-treated patients with Hashimoto thyroiditis, with normal serum TSH levels (0.3–5.0 μIU/mL) were identified (46). In this cohort, there was a positive correlation between serum T3 levels (and the T3/FT4 ratio) and thyroid volume (based on neck ultrasonography) but no correlation between T3 levels and LT4 dose. Notably, serum T3 levels were lower in patients with thyroid volumes <5 mL, 5–10 mL, and 10–15 mL, similar in patients with thyroid volumes of 15–20 mL, 20–50 mL, and 50–80 mL, and higher in patients with thyroid volume ≥80 mL, when compared to the matched controls (46). Consistent findings were obtained in LT4-treated patients who underwent a hemithyroidectomy (47). Thus, having residual thyroid tissue does seem to help maintain TH economy (and preserve T3 levels) in patients treated with LT4. This has been mathematically modeled to predict the combination doses of LT4 and LT3 required to achieve mid-normal serum levels of T4 and T3 (48). Furthermore, modeling of the published trials of combination therapy suggested that achieving higher T3 levels would allow either improvement in QOL, mood, and neurocognitive benefits or patient preference (48).

Can “over-treatment” with LT4 normalize TH signaling, and/or improve QoL?

Overtreatment with LT4 (that suppresses serum TSH) is a common strategy to minimize residual symptoms of hypothyroidism (6). The prevalence of iatrogenic subclinical hyperthyroidism in L-T4 treated patients is surprisingly elevated (49) despite not being recommended by clinical guidelines (11, 12). The question remains whether treatment with higher doses of LT4 can improve TH economy and possibly facilitate the resolution of residual symptoms (50, 51). A retrospective study of 250 LT4-treated athyreotic patients revealed that ~42% of those with normal serum TSH (0.5–5.0 μIU/mL) had FT4 levels above the reference range (0.9–1.7 ng/dL), whereas about ~26% of those patients had FT3 levels below the reference range (2.3–4.0 pg/mL) (46). In contrast, in those patients with suppressed serum TSH (<0.5 μIU/mL), ~71% had FT4 concentrations above the reference range and only 4.8% had FT3 concentrations below the reference range (46). Thus, increasing the dose of LT4 to the point that TSH becomes undetectable elevates serum T3 (presumably via D1) and substantially reduces the number of patients that remain with T3 below the reference range.

These findings were expanded in a prospective 5-year study that enrolled ~210 thyroidectomized patients, in whom TSH-suppressive doses of LT4 were more effective in improving QoL (52). Patients were stratified among three groups according to TSH levels, i.e. complete suppression (undetectable), mild suppression (detectable but <0.50 μIU/mL), and normal (0.5–5.0 μIU/mL). Significant differences were found for anxiety, impaired social and daily life, and the overall impact of thyroid disease domains. Subjects with complete TSH suppression reported the best scores in almost all domain scales. Using multiple regression analyses, FT3 levels were the best explanatory factor for the overall impact of thyroid disease on the patient’s QoL (52).

While maintaining a suppressed serum TSH seems to offer some relief of residual symptoms of hypothyroidism, this strategy is not without concerns. In a recent retrospective cohort study that used data from ~705,300 adults on LT4, with a median follow-up of 4 years, patients with TSH levels <0.10 μIU/mL had increased risk of cardiovascular mortality (compared to euthyroid individuals) after adjusting for age, sex, and cardiovascular risk factors (53). Additional longitudinal studies from large patient registries have found an association between suppressed TSH levels (<0.1 μIU/mL) and excess mortality (54, 55). Complete suppression of TSH levels (undetectable) has been associated with an increased risk of cardiovascular disease, dysrhythmias, and bone fractures, but not in patients with a low unsuppressed TSH (0.04–0.40 μIU/mL) (56). Therefore, at this time, given the available evidence for risk of adverse cardiovascular outcomes, treatment with TSH-suppressing levels of LT4 to treat residual symptoms must be done cautiously, on a case by case basis.

What is the rationale for combination therapy?

In the last 50 years, a score of clinical trials comparing both forms of therapy for hypothyroidism, i.e. LT4 vs. LT4+LT3 have been performed, and two metanalyses have recently been published (57, 58). While the details of each clinical trial varied, including types of patients, ratios of LT4 and LT3, duration, and clinical outcomes, they all had in common the fact that the dose of LT4 was reduced to accommodate the introduction of LT3 without leading to TSH suppression or thyrotoxicosis. A meta-analysis of these trials revealed that both forms of therapy performed similarly in terms of effectiveness and safety, but patients preferred therapy with LT4+LT3 (57, 58).

A more critical analysis of these studies revealed that the trials comparing therapy with LT4 vs LT4+LT3 did not specifically recruit participants with attention to patient dissatisfaction or persistent symptoms of hypothyroidism (59). The American, British, and European Thyroid Associations in a joint statement concluded for the possibility that those individuals most likely to benefit from combination therapy may not yet have been included in trials in sufficient numbers to provide adequate power for detecting a response (59). The inclusion in these trials of asymptomatic LT4-treated patients (the majority of patients with hypothyroidism) and of patients with non-thyroid-related symptoms (see below) diminished the statistical power and confused the results. Future trials should focus on triaging out these two groups and focusing on LT4-treated patients with thyroid-related symptoms.

With time, the safety record of LT3 was expanded. Mathematical modeling based on the T3 and T4 kinetics in a 70Kg individual indicates that LT3 can be used in combination with LT4 at doses not to exceed 10 mcg/day b.i.d., resulting in two daily peaks of serum T3 that remain within the normal reference range (60). There were also two critical retrospective studies examining LT3 safety. The first included approximately 400 individuals taking LT3 for up to 17 years in the Scottish region of Tayside (61), and the second was a Swedish registry study of about 575,000 individuals taking TH replacement during a median follow-up time of 8.1 years, of which roughly 11,150 were using LT3 (62). Neither of these studies identified an excess risk of cardiovascular morbidity, cancer incidence, or excess mortality in LT3-treated patients. There are also three studies in which patients were treated with DTE which did not find an excess incidence of cardiovascular risk, however, the duration of these studies was relatively shorter (63–65).

In contrast, a Korean study compared safety outcomes between ~1,400 LT3 users vs ~3,900 LT4 users with hypothyroidism, and found that the risks of heart failure and stroke were higher in LT3 users; the length of LT3 use (>52 weeks) was identified as an additional risk factor. While these are important findings, thyroid function tests (TSH, FT4, or T3) were not considered in the study, and the possibility that overtreatment with LT4 or LT4+LT3 leading to TSH suppression could not be investigated (66). Nonetheless, the study serves as a reminder that careful LT3 titration and follow-up are needed for patients on combination therapy (no safety data are available for children, pregnant women, or patients with significant cardiovascular disease; see (12, 67) for LT4 and LT3 regimens and detailed safety recommendations). Safety concerns with LT3 should decrease even further once slow-release T3 formulations currently under development become clinically available (68, 69).

A single center recently performed a prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to LT4, LT4+LT3, or DTE treatment arms, for 22 weeks (63). When focusing on the whole group of patients, there were no differences in the post-treatment scores of QoL questionnaires, and cognitive and depression tests, except for a minor increase in heart rate caused by DTE; serum TSH remained within the reference range across all treatment arms. Treatment preference was not different and there were no interferences of secondary parameters in any of the outcomes.

However, a subgroup analysis of the most symptomatic patients on LT4 (upper tertile) revealed a strong preference for either treatment arm that contained T3. These patients also had improved QoL, cognitive, and mood performance in response to therapy with T3. Overall, these results confirm the prediction put forward by the joint statement that, as a group, outcomes were similar among patients taking LT4, LT4+LT3, or DTE. However, the subgroup of patients most symptomatic on LT4 exhibited strong preference and responded positively to therapy with LT4+LT3 or DTE (63).

Similar results were obtained in an open-labeled trial that included 31 consecutive patients with hypothyroidism that exhibited a lack of improvement in symptoms while on LT4 (70). We are aware that large multicentric studies comparing LT4 with LT4+LT3 and DTE have been completed (71–73), are in the recruiting phase (ClinicalTrials.gov Identifier: NCT05412979), or are being planned; hence, more extensive data should be available in the near future.

Non-thyroid-related factors in LT4-treated patients with residual symptoms

Persistent symptoms in patients with hypothyroidism kept on “adequate” hormonal replacement with LT4 could be explained by non-thyroid-related factors (Table 1). Just the knowledge of carrying a chronic disease that requires treatment for life in itself can play a role in the development of mood and QoL symptoms. It has been the experience of many clinicians that finding and treating these factors leads to clinical improvement at least as often as trying combination therapy. The importance of recognizing and diagnosing these comorbidities cannot be overstated, especially with many patients feeling unheard and frequently being told by their endocrinologists that this investigation is outside of their scope of practice.

Table 1.

Initial approach to LT4-treated patients with residual symptoms.

Following a standard physical examination and biochemical evaluation, including electrolyte levels, renal function, calcium level, liver function tests, and complete blood count, we consider:
Most common co-morbidities to consider	When to suspect it	Initial Diagnostic Tests
Iron deficiency	• All women especially during reproductive age • Vegetarian diet • Microcytic anemia • h/o celiac disease or atrophic gastritis or H/Pylori • h/o bariatric surgery • h/o GI bleeding	Check level of Ferritin If low, the diagnosis is confirmed. If normal, but the clinical evidence is strong, check iron and total iron binding capacity (TIBC) and calculate transferrin saturation (TSAT); a low TSAT will confirm the diagnosis.
Vit B12, folate deficiency	In all patients who complain mainly of cognitive dysfunction. • Macrocytic anemia • Vegetarian diet • Metformin therapy • h/o bariatric surgery • Peripheral neuropathy, abnormal gait etc • Neuropsychiatric changes	Vit B12 and folate level. If very low the diagnosis is confirmed. If borderline check MMA and homocysteine. If both (MMA and homocysteine) are increased, Vit B12 deficiency is confirmed. If only homocysteine is elevated Folate deficiency is confirmed.
Sleep apnea	• History of excessive daytime sleepiness • History of loud snoring, witnessed apnea, etc	Refer patient to sleep study
Overweight/Obesity	Clinical diagnosis	BMI
Perimenopause, menopause	Clinical diagnosis.	Measurement of FSH level to confirm the diagnosis may be needed
Celiac disease	• In patients with Hashimoto’s thyroiditis (or other autoimmune diseases) • First and second degree relative with celiac diseaas • GI or extra-GI symptoms (e.g. unexplained iron, folate, vit B12 or vit D deficiencies)	Tissue transglutaminase IgA Antibody and IgA levels.

It is therefore important for physicians to conduct a comprehensive evaluation of each patient, with consideration for the presence of co-morbidities with symptoms that may be indistinguishable from those of hypothyroidism. Contrasting the timing of the diagnosis of hypothyroidism with the start of symptoms might help establish a potential cause-effect relationship. Whether a patient has always experienced residual symptoms once placed on LT4 as opposed to symptoms that only developed after years of treatment with LT4 might be informative, as well.

In addition to the general approach to symptomatic LT4-treated patients, we should also consider that Hashimoto thyroiditis, one of the main causes of primary hypothyroidism, may have a clinical impact that goes beyond a reduction in TH levels. Even when thyroid function tests are within the normal range, positivity for thyroid peroxidase (TPO) antibodies has been linked with fertility issues in women, an increased risk of miscarriages (74, 75), and decrements of QoL (76–79). In patients with Hashimoto’s thyroiditis and residual symptoms that were biochemically euthyroid on hormone replacement, total thyroidectomy reduced the level of anti-TPO antibodies and improved QoL when compared with a control group (80). While these studies have several limitations (safety, effectiveness, and practicality of this approach must be further evaluated given the relatively higher difficulty and complications from thyroidectomy in the setting of severe lymphocytic thyroiditis), they highlight the potential role played by the autoimmune process per se in the genesis of residual symptoms (81).

While we await a more approachable medical treatment to reduce TPO titers (rather than total thyroidectomy (82)) and further the investigation of their potential role in residual symptoms, some studies suggest that selenium supplementation (80–200 mcg daily for at least 3 months; RDA for selenium is 55 mcg daily and the upper tolerable dose is 400 mcg/day), with or without myo-inositol (600 mg daily), can attenuate the autoimmune process, reducing the level of TPO and TG antibodies and improve thyroid functions tests in patients with Hashimoto’s disease (83–86). However, these and other supplemental treatments remain investigational and not a part of the standards of care in clinical guidelines. In addition, more investigation is also needed (i) to both confirm the potential role of TPO antibodies in the genesis of residual symptoms in biochemically euthyroid patients, and (ii) to suggest monitoring TPO levels in clinical practice.

How should we approach LT4-treated patients with residual symptoms of hypothyroidism?

The complexity and multifaceted nature of the residual symptoms of hypothyroidism suggest that not a single approach can resolve all issues in all patients. In our practice, the following points have been identified as important:

1. Acknowledge to the patient that even though LT4 is effective for most patients with hypothyroidism, a small number of patients may remain symptomatic despite having normal serum TSH levels. Many such patients have moved their care among multiple physicians and may be frustrated. So, being attentive to their needs is particularly helpful.

2. Confirm that the patient has hypothyroidism from prior thyroid function tests, if available. Recent studies have identified an “epidemic” of LT4 prescriptions for individuals with normal serum TSH levels. Specifically, up to 1/3 of LT4-treated patients remain euthyroid after LT4 discontinuation (87), and ~25% of the new LT4 starts on a year-over-year basis have normal TSH and FT4 levels before LT4 start (88). Thus, if needed, LT4 should be withdrawn so that an adequate elevation in serum TSH can be documented.

3. Ensure the patient is on adequate LT4 dosage. A surprisingly large number of LT4-treated patients have been found to have off-target serum TSH levels in cross-sectional studies ((89–92).

4. Investigate other conditions and comorbidities (including psychological comorbidities) that can cause or contribute to residual symptoms. From a practical standpoint, we routinely ask for a complete metabolic panel and complete blood count, which screens for conditions such as anemia, and renal and liver disease. We also check for ferritin levels, especially in women during reproductive age, and we treat it if below 50 ng/ml (iron deficiency has been associated with symptoms even in the absence of anemia (93, 94)). It has been our experience that this approach often time resolves some of the symptoms and improves overall stamina.

   We treat patients will vitamin D deficiency (<20 mg/mL) and if no improvement is obtained, then we routinely screen for celiac disease with tissue transglutaminase IgA, including those patients with a history or clinic suggestive of iron deficiency. We routinely check for vitamin B12 levels in patients that are on a vegetarian diet, on metformin therapy, or have a history of bariatric surgery, macrocytic anemia, peripheral neuropathy, or gait instability, and in patients that have neuropsychiatric changes. Both vitamin B12 and folate deficiency can cause cognitive dysfunction, so we screen for both in all LT4-treated patients who complain of “brain fog”, and/or cognitive dysfunction (95). If one or both (vitamin B12 and folate) are near the lower limit of normal, then we check the levels of methylmalonic (MMA) acid and homocysteine. Increased levels of MMA and homocysteine confirm deficiency of vitamin B12 (if only homocysteine levels are increased, then folate deficiency is confirmed) and the need for adequate treatment. HbA1C levels are used as a screening tool whenever indicated. Given that being overweight (or sedentary) is one of the indications for screening, we would argue that almost all patients should be screened. Perimenopause and menopause are investigated clinically and may require measuring FSH levels (96). Estrogen replacement therapy should be considered and discussed with symptomatic patients if appropriate. Being overweight and obese are diagnosed clinically and should be addressed accordingly. We also refer patients for sleep studies if fatigue and/or brain fog are the main complaints and when the clinical history is suggestive (overweight/obesity, history of snoring, falling asleep during the day) (97).

5. Attempt combination therapy with LT4+LT3 (as described below) if it is unequivocal that the patient has hypothyroidism, did not fully benefit from therapy with LT4, and no other explanation for the residual symptoms can be found.

In our practice, we follow the general guidance provided in two outstanding publications to place patients on therapy with LT4+LT3 (12, 98). The starting regimen requires a decrease in the LT4 dose and replacement with LT3. There are multiple methods to calculate the new doses (12, 98). A reasonable starting point is to aim at a L-T4/L-T3 dose ratio similar to what the thyroid gland physiologically produces, which ranges between 13–20:1. For example if a patient is biochemically euthyroid on 100 mcg of L-T4/day, then the dose of L-T3 is calculated by dividing 100/20 = 5 mcg (the dose is split into two daily doses, the second dose is about 8 hrs after the first one or 1–2 hours before dinner). The new dose of L-T4 will be 100 mcg minus the dose of L-T3 × 3 [100-(5×3) = 85 mcg] (round off 88 mcg ). So a patient on 100 mcg daily of L-T4 can be switched to 88 mcg daily of L-T4 plus 2.5 mcg twice daily.

Most of the methods suggested take into account the initial dose of L-T4 even when it is very low (for example 25–50 mcg/day). In such cases, however, especially in older patients, physicians should carefully consider the initial TH levels to confirm the indication of treatment. The amount of LT3 can be adjusted up depending on symptoms and the serum TSH (as long as the ratio is not more than 13:1).

Measure serum TSH, FT4, and T3 fasting and 2–4 h post-dose (expected peak of serum T3). Serum TSH and T3 levels must be kept within the reference range, otherwise, an appropriate dose adjustment is necessary. Consider reducing the dose of LT4 if the peak of T3 is within the normal range but serum TSH is suppressed. If needed, adjustments in the dose of LT4 and LT3 should be done at 6-week intervals. Monitor blood pressure, pulse rate, and heart rhythm every 3–6 months for the first year of therapy, and then annually thereafter. Elevated heart rate and/or palpitations may warrant additional testing, including ECG and echocardiogram. Assessment of benefit should be performed at 6 and 12 months after combination therapy has started. Although clinical guidelines do not recommend the use of DTE, it is notable that a substantial number of our patients with hypothyroidism already come for a new patient visit on a regular DTE regimen. DTE contains slightly more T3 than we would otherwise prescribe using synthetic TH. DTE is prescribed in grains: 1 grain is 65 mg of DTE and most commonly contains 38 mcg of T4 and 9 mcg of T3, with a margin of error of ±10% (67).

1. To switch patients between LT4 and DTE, we utilize the conversion table defined previously (63) (for example 100 mcg of LT4 is equivalent to 67.5 mg of DTE). The conversion chart proposed by the United States Pharmacopeia slightly overestimates the DTE potency, as it was recently found in the first clinical trial that tested the chart (71).

Conclusion

Patients with hypothyroidism appropriately treated with LT4 (that have a normal serum TSH) may remain symptomatic. This has been documented in several studies and should be discussed with patients starting therapy for hypothyroidism or those considering definitive treatment for thyroid disease. The mechanistic explanation for the residual symptoms is under current investigation, but it could involve a relative deficiency of T3. New trials focusing on LT4-treated patients that remained symptomatic revealed preference and superiority of combination therapy containing LT4+LT3. Given the new long-term safety data available for LT3, a recent joint statement of the American, British, and European Thyroid Associations recommends that a trial with combination therapy be offered to patients with hypothyroidism who did not fully benefit from therapy with LT4.

Highlights.

Bullet points

1. Levothyroxine (LT4) at doses that maintain serum thyrotropin (TSH) levels eliminates, signs and symptoms of overt hypothyroidism thanks to the endogenous activation of thyroxine (T4) to triiodothyronine (T3), the biologically active thyroid hormone.

2. A small percentage of the patients (10–20%) exhibit residual symptoms of hypothyroidism, despite having normal serum TSH levels. These symptoms include cognitive, mood, and metabolic deficits, with a significant impairment in psychological well-being and quality of life.

3. It is not entirely clear what makes these patients susceptible to experiencing these symptoms, but it could be a relative deficiency of T3, hence the justification for combination therapy with LT4+liothyronine (LT3).

4. A score of clinical trials comparing therapy with LT4 versus LT4+LT3 concluded that both are safe and equally effective (neither is superior), but these trials failed to recruit a sufficiently large number of patients with residual symptoms.

5. New clinical trials that considered LT4-treated symptomatic patients revealed that such patients benefit from and prefer therapy containing LT4+LT3; desiccated thyroid extract (DTE) has also been used with similar results.

Clinical Relevance

This article discusses the shortcomings of therapy with LT4, provides a mechanistic explanation for the incomplete normalization of thyroid hormone signaling, and details how to approach patients with residual symptoms of hypothyroidism. The article also discusses the effectiveness and safety of combination therapy and offers a practical approach to initiate patients on therapy with LT4+LT3.