Emerging Therapies in Hypothyroidism

More recent studies with a larger number of subjects confirmed the association between the DIO2 polymorphism and reduced effectiveness of LT4.

“However, more recent studies with a larger number of subjects confirmed the association between the DIO2 polymorphism and the reduced effectiveness of LT4.”

• cites [31] sourceDisputed

  The Conclusions (page unavailable) describe the evidence on Thr92Ala-DIO2 as conflicting. They report lower T3 levels in LT4-treated carriers in an Italian study, but also state that a Netherlands study found no effect on response to LT4 monotherapy. The References identify the Netherlands study as a large population-based cohort, contrary to the claim that larger studies confirmed reduced LT4 effectiveness. (LLM, conf=0.85)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

In none of the scenarios of LT3 dosing described did T3 levels in the circulation cross the upper limit of normal.

“Nonetheless, in none of these scenarios did T3 levels in the circulation cross the upper limit of normal.”

• cites [50] sourceDisputed

  The Results (page not provided) explicitly predict T3 levels above the reference range in several LT3 dosing scenarios: 32%–40.4% of the time for modeled 50 mcg daily regimens, and 14% of the time for one modeled LT4/LT3 substitution. This contradicts the claim that none of the scenarios crossed the upper limit of normal. (LLM, conf=0.91)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Under certain conditions, T3 signaling may be compromised in a tissue-specific fashion while systemic thyroid function is preserved.

“Finally, there is a new understanding that, under certain conditions, T3 signaling may be compromised in a tissue-specific fashion while systemic thyroid function is preserved.”

• Also stated in: § INTRODUCTION · plain

  “Due to tissue-specific mechanisms that regulate the local conversion of T4 to T3 (ubiquitination of the type 2 deiodinase, D2), T4 is very effective in triggering the pituitary feedback mechanism and normalizing serum TSH levels.”

• cites [25] sourcePartly supported

  The Discussion (p. 5) reports signs of reduced thyroid hormone action in the brain, liver, and skeletal muscle of L-T4-treated rats despite normal serum TSH. But it also reports low serum T3 and high serum T4, so the study does not show that systemic thyroid function was fully preserved; the preserved measure was TSH. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [26] sourcePartly supported

  The Discussion describes a possible difference between central and peripheral T4-to-T3 conversion in LT4-treated patients, consistent with tissue-specific differences despite a TSH response. But it says that T3 action in other tissues was not evaluated, so it does not establish compromised tissue T3 signaling while systemic thyroid function is preserved. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Levothyroxine (LT4) is effective for most patients with hypothyroidism.

“Levothyroxine (LT4) is effective for most patients with hypothyroidism.”

• Also stated in: § THERAPY WITH LT4 · boosted

  “there is overwhelming evidence that LT4 restores clinical and biochemical euthyroidism in the vast majority of patients with hypothyroidism.”

• cites [3] sourceSupported

Many patients who do not fully benefit from LT4 experience improved quality of life and cognition after switching to LT4+LT3.

“Many patients who do not fully benefit from LT4 experience improved quality of life and cognition after switching to LT4+LT3.”

• Also stated in: § Effectiveness · plain

  “An open-label study of consecutive symptomatic LT4-treated patients supported the benefits of combination therapy (49).”

• cites [49] sourcePartly supported

  The Abstract (p. 2) reports improved quality-of-life scores after 31 levothyroxine-unresponsive patients switched to natural desiccated thyroid (NDT), which contains LT4 and LT3. But the study evaluated NDT rather than a separately prescribed LT4+LT3 regimen, and it does not report improved cognition. The Discussion (approximately p. 11) instead notes that a cited trial found no difference in neurocognitive measurements between NDT and levothyroxine. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

A minority of patients with hypothyroidism remain symptomatic despite normalization of serum thyrotropin levels.

“However, a minority of the patients remain symptomatic despite the normalization of serum thyrotropin levels.”

• Also stated in: § THERAPY WITH LT4 · plain

  “A caveat is that LT4 is not 100% effective in restoring clinical euthyroidism in all patients with hypothyroidism, despite the normalization of serum TSH levels (32).”

• cites [5] sourceNot checked — no full text of the source
• cites [6] sourceNot checked — no full text of the source
• cites [7] sourceNot checked — no full text of the source
• cites [32] sourceSupported

Patients with hypothyroidism prefer LT4+LT3 therapy over LT4 alone.

“Randomized clinical trials including all types of patients with hypothyroidism revealed that combination levothyroxine and liothyronine (LT4+LT3) therapy is safe and is the preferred choice of patients versus LT4 alone.”

• Also stated in: § INTRODUCTION · plain

  “The fact that patients preferred LT4+LT3, as evidenced in two recent meta-analyses (15, 16), was not sufficient to challenge the standing of LT4 as the standard of care.”

• Also stated in: § Effectiveness · boosted

  “Last, both analyses concluded that patients significantly preferred LT4+LT3 (16).”

• cites [15] sourceSupported
• cites [16] sourceSupported

The standard of care for hypothyroidism is to restore thyroid hormone levels with the intent of normalizing tissue content of thyroid hormones and expression of thyroid-hormone-responsive genes in all tissues.

“For the most part, the standard of care for the treatment of hypothyroidism is to restore TH levels with the intent of normalizing the tissue content of TH and the expression of TH-responsive genes in all tissues (3).”

• cites [3] sourcePartly supported

  The Discussion of the clinical literature says the goals of levothyroxine replacement are euthyroidism and normalization of circulating TSH and thyroid hormones. The Mechanistic background explains that thyroid hormone regulates responsive genes in tissues, but the guidelines do not state that normalizing hormone content and gene expression in all tissues is the standard-of-care treatment goal. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Combination levothyroxine and liothyronine (LT4+LT3) therapy is safe in patients with hypothyroidism.

“Randomized clinical trials including all types of patients with hypothyroidism revealed that combination levothyroxine and liothyronine (LT4+LT3) therapy is safe and is the preferred choice of patients versus LT4 alone.”

• Also stated in: § Safety · plain

  “analysis of 18 RCTs found that similar proportions of adverse events or reactions were observed between LT4 and LT4+LT3 treatment groups (16).”

• cites [16] sourcePartly supported

  The Conclusion (page not specified) says adverse events and reactions appeared similar with LT4+LT3 and LT4 alone, but explicitly calls this a narrative observation. The Results report adverse-event withdrawals in both groups, and the Discussion notes that follow-up of 12 weeks or less in over half the studies may be insufficient to assess safety. The evidence therefore supports comparable observed short-term harms, not an unqualified claim that combination therapy is safe. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

The American, British, and European Thyroid Associations, as well as the Society for Endocrinology, agree that serum T3 levels might not be restored in all patients even when serum TSH and free T4 levels have been normalized.

“They also agree that serum T3 levels might not be restored in all patients, even when serum TSH and free T4 levels have been normalized (32).”

• cites [32] sourcePartly supported

  The Methods section reports that patients receiving levothyroxine can have low serum T3 despite comparable or normalized TSH. It describes free T4 as elevated rather than establishing that it, too, has normalized. The Introduction identifies a joint conference of the American, British, and European Thyroid Associations, but does not establish agreement by the Society for Endocrinology on this point. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Two to three hours after administering a T3-containing tablet, serum T3 reaches a peak level that depends on baseline fasting values and the dose of T3 administered.

“Two to three hours after administering a T3-containing tablet, serum T3 will reach a peak level that depends on the baseline (fasting) values and the dose of T3 administered.”

• cites [48] sourceSupported

It is unlikely that any of the randomized controlled trials comparing LT4 versus LT4+LT3 was sufficiently powered to detect differences for symptomatic patients.

“Considering that symptomatic patients represent only 10–20% of the total population of patients with hypothyroidism, it is unlikely that any of these trials was sufficiently powered to detect differences between therapy with LT4 versus LT4+LT3 for those symptomatic patients.”

• cites [32] sourceSupported

A mouse carrying the DIO2 polymorphism exhibited signs of reduced T3 signaling in the brain that responded to therapy containing LT4+LT3.

“Later, this polymorphism was found to be associated with an approximately 40% reduction in the catalytic activity of D2 (28, 29), and a mouse carrying the DIO2 polymorphism exhibited signs of reduced T3 signaling in the brain that responded to therapy containing LT4+LT3 (28).”

• cites [28] sourceSupported

Patients with hypothyroidism kept on LT4 with a normal serum TSH exhibit a relative and sometimes absolute deficiency of T3.

“The second discovery was that patients with hypothyroidism kept on LT4, with a normal serum TSH, exhibit a relative (and sometimes absolute) deficiency of T3.”

• cites [21] sourceNot checked — no full text of the source
• cites [22] sourcePartly supported

  The Results (page not specified) report that, despite normal TSH, 29.6% of LT4-treated athyreotic patients had a low FT3/FT4 ratio and 15.2% had FT3 below the normal range. This supports relative and sometimes absolute T3 deficiency in the studied group, but the claim extends the finding to patients with hypothyroidism generally; the study examined athyreotic patients. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Replacement doses of synthetic or natural hormones can be titrated to promote normalization of serum free T4 and T3 levels without suppressing serum TSH levels.

“Replacement doses of synthetic or natural hormones can be titrated to promote these changes without suppressing serum TSH levels (43–47).”

• cites [43] sourcePartly supported

  The Study design passage (page unavailable) says doses of LT4, LT4 + LT3, and desiccated thyroid extract were adjusted to keep TSH within the normal range. Secondary Analyses (page unavailable) confirms that TSH remained normal while T3 and T4 levels changed, but it does not establish normalization of both free T4 and free T3; it reports total T3 rather than free T3. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [44] sourceNot checked — no full text of the source
• cites [45] O'Sullivan A, 2022, ThyroidNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [46] Brazg R, 2022, ThyroidNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [47] sourcePartly supported

  The Results report that TSH was within the reference range about 79% of the time in patients prescribed either synthetic levothyroxine or desiccated thyroid. The Outcome Variables section lists TSH measures only; the paper does not establish that doses were titrated to normalize free T4 and T3 without suppressing TSH. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Physicians in the United Kingdom and the United States concluded in the 1960s that only treatment with LT4+LT3 was able to resolve symptoms and restore thyroid hormone levels as assessed through protein-bound iodine levels.

“Indeed, physicians in the United Kingdom and the United States concluded back in the 1960s that only treatment with LT4+LT3 was able to resolve symptoms and restore TH levels (as assessed through protein-bound iodine levels) (12–14).”

• cites [12] sourcePartly supported

  The Abstract reports that combined T4/T3 treatment maintained patients after total thyroidectomy in a euthyroid state with protein-bound iodine in the normal range. The Introduction and discussion support its value for some patients, but not the claim that it was the only treatment able to resolve symptoms; the discussion limits the problem with T4 alone to a very small group. This paper also does not establish a conclusion by physicians in both the United Kingdom and the United States in the 1960s. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [13] sourceNot checked — no full text of the source
• cites [14] sourceNot checked — no full text of the source

A second meta-analysis of 18 studies (883 patients) concluded that compared with LT4 monotherapy, LT4+LT3 combination therapy was equally effective in improving psychological health.

“A second meta-analysis of these 18 studies (883 patients) also concluded that compared with LT4 monotherapy, LT4+LT3 combination therapy was equally effective in improving psychological health (15).”

• cites [15] sourceSupported

LT4 is not 100% effective in restoring clinical euthyroidism in all patients with hypothyroidism, despite normalization of serum TSH levels.

“A caveat is that LT4 is not 100% effective in restoring clinical euthyroidism in all patients with hypothyroidism, despite the normalization of serum TSH levels (32).”

• cites [32] sourceSupported

Maintaining normal plasma T3 levels is the main directive of the hypothalamus-pituitary-thyroid axis.

“The first discovery was that maintaining normal plasma T3 levels is the main directive of the hypothalamus-pituitary-thyroid (HPT) axis (17).”

• cites [17] sourcePartly supported

  In 'Limitations of levothyroxine monotherapy' (page unavailable), the paper describes T4 and T3 feedback on the hypothalamus and pituitary. It does not say that maintaining normal plasma T3 is the axis’s main directive; 'Normalization of T3 levels in hypothyroidism' also reports that normal TSH can coexist with low serum T3 during levothyroxine treatment. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

A recent meta-analysis of 18 randomized controlled trials comparing LT4+LT3 versus LT4 for adult patients with hypothyroidism obtained low- to moderate-certainty evidence that no differences exist in treatment effect between therapies regarding clinical status, quality of life, psychological distress, depressive symptoms, and fatigue.

“A recent meta-analysis of 18 RCTs comparing LT4+LT3 versus LT4 for adult patients with hypothyroidism examined clinical outcomes and patient preferences (16). The authors obtained low- to moderate-certainty evidence that no differences exist in treatment effect between therapies regarding clinical status, quality of life, psychological distress, depressive symptoms, and fatigue.”

• cites [16] sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

An undisputed result of combination therapy with synthetic LT4 and LT3 or with desiccated thyroid extract is the normalization of serum free T4 levels and serum T3 levels.

“An undisputed result of combination therapy with synthetic LT4 and LT3 or with DTE is the normalization of the serum free T4 levels (which are relatively higher in LT4-treated patients) and serum T3 levels (which are relatively lower in LT4-treated patients).”

• cites [43] sourcePartly supported

  The Secondary Analyses report that DTE and LT4+LT3 raised fasting serum T3 and lowered serum T4 relative to LT4 alone; the Discussion likewise describes lower T3 and higher T4 on LT4. The paper does not establish that both serum free T4 and T3 were normalized by either combination therapy. The normal-range findings cited in these passages concern TSH and the T4/T3 ratio, not both hormone levels. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [44] sourceNot checked — no full text of the source
• cites [45] O'Sullivan A, 2022, ThyroidNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [46] Brazg R, 2022, ThyroidNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [47] sourceCould not verify

  The Outcome Variables and Results sections assess TSH values and their stability in patients prescribed levothyroxine or desiccated thyroid; they do not report normalization of serum free T4 or T3. Searches for free T4, T3, and LT4/LT3 combination therapy found no passage addressing those claims. Page numbers were not available in our copy. (LLM, conf=0.77)

  Experimental — accuracy not yet measured

For over 50 years, LT4 has been the standard of care for the treatment of hypothyroidism.

“For over 50 years now, LT4 has been the standard of care for the treatment of hypothyroidism (39).”

• cites [39] sourcePartly supported

  The section ‘Establishment of LT4 as the standard of care for hypothyroidism’ explicitly calls LT4 the standard of care. The Conclusions say it emerged as the mainstay in the second half of the 20th century, but the paper does not establish that it had held that status for over 50 years by 2022. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

The American, British, and European Thyroid Associations, as well as the Society for Endocrinology, agree that therapy with LT4 might leave a substantial number of patients (10-20%) with residual symptoms of hypothyroidism.

“Currently, the American, British, and European Thyroid Associations, as well as the Society for Endocrinology, agree that therapy with LT4 might leave a substantial number of patients (10–20%) with residual symptoms of hypothyroidism (32, 33).”

• cites [32] sourcePartly supported

  The Introduction and Methods (page numbers unavailable) acknowledge that some patients taking LT4 remain dissatisfied or have persistent hypothyroid symptoms. The paper describes a joint conference of the American, British, and European Thyroid Associations, but the passages do not establish the claimed 10–20% prevalence or an agreement by the Society for Endocrinology. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [33] sourcePartly supported

  The Background (p. 2) says some levothyroxine-treated patients have persistent symptoms, and section 6 (p. 5) describes the American, European, and British thyroid associations acknowledging patients whose needs are not met by levothyroxine alone. This joint British Thyroid Association/Society for Endocrinology statement does not give the claimed 10–20% figure; its Summary (p. 8) calls the group a “small minority.” (LLM, conf=0.86)

  Experimental — accuracy not yet measured

The Thr92Ala polymorphism in DIO2 is associated with an approximately 40% reduction in the catalytic activity of D2.

“Later, this polymorphism was found to be associated with an approximately 40% reduction in the catalytic activity of D2 (28, 29), and a mouse carrying the DIO2 polymorphism exhibited signs of reduced T3 signaling in the brain that responded to therapy containing LT4+LT3 (28).”

• cites [28] sourcePartly supported

  The Results (p. 6) report that intact cells expressing Ala92-D2 produced approximately 30% less T3 than cells expressing Thr92-D2, supporting reduced T4-to-T3 conversion. They do not report an approximately 40% reduction in catalytic activity; D2 activity measured in cell sonicates was indistinguishable between the variants. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [29] sourceNot checked — no full text of the source

During the last 50 years, scores of clinical trials have compared the effectiveness and safety of LT4 monotherapy versus LT4+LT3 combination therapy in the treatment of hypothyroidism.

“During the last 50 years, scores of clinical trials have compared the effectiveness and safety of LT4 monotherapy versus LT4+LT3 combination therapy in the treatment of hypothyroidism (48).”

• cites [48] sourcePartly supported

  The trial summaries in our copy (labelled Abstract; page unavailable) describe 16 once-daily and four twice-daily trials comparing LT4+LT3 with LT4 alone, including effectiveness and safety measures. They support the substance of the comparison, but document about 20 trials—not clearly “scores”—and do not establish the claimed 50-year span. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Symptomatic patients represent only 10-20% of the total population of patients with hypothyroidism.

“Considering that symptomatic patients represent only 10–20% of the total population of patients with hypothyroidism, it is unlikely that any of these trials was sufficiently powered to detect differences between therapy with LT4 versus LT4+LT3 for those symptomatic patients.”

• cites [32] sourceCould not verify

  The Methods discuss patients with persistent symptoms, but give no estimate that they constitute 10–20% of all patients with hypothyroidism. The Methods’ statement that trials would be underpowered if a response were expected in only 20% of participants concerns treatment response, not the prevalence of symptoms (searched: 10–20%, 10% of patients, persistent symptoms). (LLM, conf=0.76)

  Experimental — accuracy not yet measured

The proposed role played by the Thr92Ala DIO2 polymorphism was not reproduced in all populations.

“The proposed role played by the Thr92Ala DIO2 polymorphism was not reproduced in all populations (30).”

• cites [30] sourceSupported

Synthetic T3 or the T3 contained in desiccated thyroid extract is rapidly absorbed through the gastrointestinal tract after oral administration.

“Synthetic T3 or the T3 contained in DTE is rapidly absorbed through the gastrointestinal (GI) tract after oral administration.”

• cites [48] sourceSupported

Compounding factors such as genetic background and comorbidities might impair even further the effectiveness of therapy with LT4, leading to residual symptoms despite normalization of serum TSH levels.

“These observations led to the idea that compounding factors such as genetic background and comorbidities might impair even further the effectiveness of therapy with LT4, leading to residual symptoms despite the normalization of serum TSH levels (31).”

• cites [31] sourcePartly supported

  The Conclusions propose a genetic or other patient-specific “second hit” that could compound relatively low T3 levels and contribute to persistent symptoms despite normal TSH. They also name coexisting chronic diseases as possible alternative causes of similar symptoms, but do not establish that comorbidities impair LT4 effectiveness. (LLM, conf=0.81)

  Experimental — accuracy not yet measured

An open-label study of consecutive symptomatic LT4-treated patients supported the benefits of combination therapy.

“An open-label study of consecutive symptomatic LT4-treated patients supported the benefits of combination therapy (49).”

• cites [49] sourcePartly supported

  The Results and Conclusion (pp. 3, 14) report symptomatic and quality-of-life improvements after natural desiccated thyroid (NDT) in people unresponsive to levothyroxine, while acknowledging that the study was unblinded and had no comparator. The Introduction (p. 5) distinguishes NDT from levothyroxine/liothyronine combination therapy, so the findings support a potential benefit of NDT, not combination therapy generally. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

In a recent crossover randomized controlled trial comparing LT4, LT4+LT3, and desiccated thyroid extract, when the whole group of 75 patients was analyzed, no differences were observed among the three therapies.

“A hint that this is indeed the case was obtained in a recent crossover RCT comparing therapy with LT4, LT4+LT3, and DTE (43). When the whole group of 75 patients was analyzed, no differences were observed among the three different therapies.”

• cites [43] sourcePartly supported

  The Study design and Discussion passages describe a randomized crossover comparison of LT4, LT4+LT3, and DTE in 75 patients. The Primary Outcome Measures passage reports no differences in symptom, mood, or cognitive scores across treatments. But Secondary Analyses reports differences in thyroid hormone levels and a small increase in heart rate with DTE, so the unqualified statement that no differences were observed is too broad. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

The randomized controlled trials comparing LT4+LT3 versus LT4 might not have enrolled large enough numbers of patients who remained symptomatic while on LT4.

“A caveat associated with these RCTs is that they might not have enrolled large enough numbers of patients who remained symptomatic while on LT4 (32).”

• cites [32] sourceSupported

In that crossover randomized controlled trial, when the analysis was broken down according to the intensity of symptoms while on LT4, only patients with the highest level of symptoms while on LT4 benefited from either LT4+LT3 or desiccated thyroid extract.

“However, when the analysis was broken down according to the intensity of symptoms while on LT4, it became clear that only those patients with the highest level of symptoms while on LT4 benefited from either LT4+LT3 or DTE.”

• cites [43] sourceSupported

There is overwhelming evidence that LT4 restores clinical and biochemical euthyroidism in the vast majority of patients with hypothyroidism.

“Although regulatory agencies such as the US Food and Drug Administration did not require an RCT for the full approval of LT4, there is overwhelming evidence that LT4 restores clinical and biochemical euthyroidism in the vast majority of patients with hypothyroidism.”

• cites [3] sourcePartly supported

  The Background, Objectives, and Rationale section says LT4 resolves hypothyroid signs and symptoms in the majority of patients. The Discussion of the clinical literature identifies biochemical normalization as a treatment goal, but the passages do not establish that the vast majority achieve both clinical and biochemical euthyroidism; the recommendation rates the evidence as moderate rather than overwhelming. Page numbers are unavailable in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Sustained serum T3 levels were not observed with other formulations prepared with microcrystalline cellulose and magnesium stearate (BCT303).

“However, sustained serum T3 levels were not observed with other formulations prepared with microcrystalline cellulose and magnesium stearate (BCT303) (56).”

• cites [56] sourceSupported

In hypothyroid rats, T3 clearance rate did not differ between poly-zinc-LT3 and LT3 treatment.

“The T3 clearance rate did not show differences between poly-zinc-LT3- and LT3-treated rats.”

• cites [63] sourceSupported

In hypothyroid rats, the decline in elevated TSH after poly-zinc-LT3 was delayed by ~4 h compared with LT3.

“TSH levels, which were elevated, declined rapidly after LT3 administration, but the decline was delayed by ~4 h in poly-zinc-LT3-treated rats.”

• cites [63] sourceSupported

Exposure to human TSH causes these cells to organize in a 3D follicular architecture.

“Exposure to human TSH causes these cells to organize in a 3D follicular architecture that was grafted under the kidney capsules of hypothyroid mice.”

• cites [67] sourceSupported

T3 is rapidly metabolized through inner ring deiodination to 3,3′-T2, with a half-life of 12-24 hours.

“T3 is also rapidly metabolized through inner ring deiodination to 3,3′-T2, with a half-life of 12–24 h.”

• cites [48] sourcePartly supported

  The Pharmacokinetics of LT3 passage (labeled Abstract in our copy; page unavailable) reports rapid changes in circulating T3 after oral dosing and a slow elimination-phase half-life of approximately 23 hours, within the claimed 12–24-hour range. The Pharmacodynamics passage says T3 is rapidly metabolized, but our copy does not identify inner-ring deiodination to 3,3′-T2 as the pathway. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

The 2014 American Thyroid Association clinical guidelines for the treatment of hypothyroidism called for the development of new T3 formulations that would avoid the swings in serum T3 levels observed with current T3-containing formulations.

“While the multiple RCTs and large retrospective studies show that therapy containing T3 is as safe as therapy with LT4, the 2014 American Thyroid Association clinical guidelines for the treatment of hypothyroidism called for the development of new T3 formulations that would avoid the swings in serum T3 levels observed with the current T3-containing formulations, i.e., LT3 or DTE.”

• cites [3] sourceCould not verify

  The Conclusions call for research on serum T3 and treatment alternatives, but do not call for new T3 formulations to prevent serum-level swings. The table of contents points to a later section on standard and sustained-release T3 (p. 1713), but that discussion is missing from our truncated copy. Searches for T3 formulations, sustained release, and serum T3 fluctuations did not resolve the claim. (LLM, conf=0.70)

  Experimental — accuracy not yet measured

Using mouse embryonic stem cells, primordial lung and thyroid progenitors were obtained by manipulating TGFβ, BMP, and FGF signaling pathways.

“Using mouse embryonic stem cells (ESCs), primordial lung and thyroid progenitors were obtained by manipulating the transforming growth factor β, bone morphogenic protein, and fibroblast growth factor signaling pathways (66).”

• cites [66] sourceSupported

In healthy volunteers, the areas under the curve for poly-zinc-LT3 and LT3 were similar.

“Remarkably the areas under the curves were similar, indicating that similar amounts of T3 were absorbed but with substantially different PK.”

• cites [64] sourceSupported

In healthy volunteers, after poly-zinc-LT3 administration, serum T3 levels at 24 h still exceeded half of Cmax.

“This was followed by a lower but much longer plateau; by 24 h, serum T3 levels still exceeded half of Cmax.”

• cites [64] sourceSupported

Multiple randomized controlled trials and large retrospective studies show that therapy containing T3 is as safe as therapy with LT4.

“While the multiple RCTs and large retrospective studies show that therapy containing T3 is as safe as therapy with LT4, the 2014 American Thyroid Association clinical guidelines for the treatment of hypothyroidism called for the development of new T3 formulations that would avoid the swings in serum T3 levels observed with the current T3-containing formulations, i.e., LT3 or DTE.”

• cites [16] sourcePartly supported

  The Results section (page not provided) says adverse-event rates in the reviewed trials did not appear to differ between LT4/LT3 combination therapy and LT4 monotherapy, but no statistical comparison was performed. The paper reviewed trials, not large retrospective studies, and its Conclusion describes the safety finding as narrative rather than establishing that T3-containing therapy is equally safe. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [51] sourceNot checked — no full text of the source
• cites [52] sourceNot checked — no full text of the source

The frequency of adverse events and reactions among patients taking LT4, LT4+LT3, or desiccated thyroid extract was similar in two single-center crossover randomized controlled trials involving approximately 150 patients.

“The frequency of adverse events and reactions among patients taking LT4, LT4+LT3, or DTE was similar in two single-center crossover RCTs involving ~150 patients (43, 44).”

• cites [43] sourcePartly supported

  The Results section (‘Adverse drug reactions’; page unavailable) reports no adverse effects with LT4, LT4+LT3, or DTE in this 75-patient crossover trial. The Introduction and Discussion mention a previous LT4-versus-DTE trial, but our copy does not establish comparable adverse-event rates across two trials involving approximately 150 patients. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [44] sourceNot checked — no full text of the source

Analysis of 18 randomized controlled trials found that similar proportions of adverse events or reactions were observed between LT4 and LT4+LT3 treatment groups.

“On the contrary, analysis of 18 RCTs found that similar proportions of adverse events or reactions were observed between LT4 and LT4+LT3 treatment groups (16).”

• cites [16] sourcePartly supported

  The Results section reports that adverse-event incidence did not appear to differ between treatments, but says this was a narrative judgment without a statistical comparison. It also identifies 18 included studies, of which 17 were RCTs and one was quasiexperimental; adverse-event data came from subsets of those studies, not all 18. (LLM, conf=0.92)

  Experimental — accuracy not yet measured

Overexpression of transcription factors NKX2.1 and PAX8 in these progenitors led to fully differentiated follicular cells expressing thyroid-specific genes such as TSH receptor, sodium/iodide symporter, and thyroglobulin.

“The subsequent overexpression of the transcription factors NKX2.1 and PAX8 (67) led to fully differentiated follicular cells that express thyroid-specific genes such as TSH receptor, sodium/iodide symporter, and thyroglobulin.”

• cites [67] sourcePartly supported

  In “In vitro thyroid cells differentiation,” the paper reports that NKX2.1 and PAX8 co-overexpression up-regulated Tshr, Slc5a5 (NIS), and Tg and drove cells toward a thyroid follicular-cell lineage. But the same section and “In vitro formation of functional follicles” say subsequent TSH treatment was vital to complete follicular maturation; overexpression alone did not produce the fully developed follicular structures implied by the claim. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

In healthy volunteers, TSH levels were similarly reduced in poly-zinc-LT3 and LT3 groups.

“TSH levels were similarly reduced in both groups (64).”

• cites [64] sourceSupported

In obese individuals, surgical liver biopsies identified sets of downregulated genes that were previously demonstrated to be positively regulated by T3.

“Furthermore, the study of surgical liver biopsies of obese individuals identified sets of downregulated genes previously demonstrated to be positively regulated by T3 (74).”

• cites [74] sourceSupported

A high-fat diet can reduce expression of transcriptional regulators necessary for T3 signaling in the liver.

“For example, there is considerable evidence that a high-fat diet can reduce the expression of transcriptional regulators that are necessary for T3 signaling in the liver (73–75).”

• cites [73] sourceNot checked — no full text of the source
• cites [74] sourcePartly supported

  The Results section reports reduced expression of several thyroid-receptor coactivators or corepressors in the livers of obese humans. It also reports that high-fat feeding reduced thyroid-responsive gene expression and blunted the response to T3 in mice, but does not show that the diet reduced expression of those transcriptional regulators. No page number is available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [75] sourcePartly supported

  The Discussion (page unavailable) reports impaired thyroid-hormone signaling in the liver of high-fat-fed mice and suggests that reduced levels of Pgc-1, a TR coactivator, might explain it. It calls that mechanism unknown, however, and does not establish reduced expression of multiple transcriptional regulators necessary for T3 signaling. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Transplantable thyroid organoids derived from human ESCs restored plasma thyroid hormone levels in athyreotic mice.

“More recently, transplantable thyroid organoids derived from human ESCs restored plasma TH levels in athyreotic mice (69).”

• cites [69] sourceSupported

For some patients, the success of LT4 was limited by persistence of residual cognitive symptoms and decrements in quality of life.

“For some patients, however, the success story was limited by the persistence of residual cognitive symptoms and decrements in the quality of life (5–7).”

• cites [5] sourceNot checked — no full text of the source
• cites [6] sourceNot checked — no full text of the source
• cites [7] sourceNot checked — no full text of the source

The change to therapy with LT4 was introduced without formal randomized controlled trials to test its effectiveness and safety.

“The change to therapy with LT4 was introduced without formal randomized controlled trials (RCTs) to test the effectiveness and safety of LT4.”

• cites [4] Bianco AC. 2022. Rethinking Hypothyroidism . Chicago: Univ. Chicago Press. 311 pp.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Patients with the Thr92Ala polymorphism in DIO2 exhibited better clinical outcomes when treated with LT4+LT3 as opposed to LT4 alone.

“The third discovery was that patients with the Thr92Ala polymorphism in DIO2, the gene encoding D2, exhibited better clinical outcomes when treated with LT4+LT3 as opposed to LT4 alone (27).”

• cites [27] sourceNot checked — no full text of the source

To the authors' knowledge, not a single study has been published in which T3-containing treatment for hypothyroidism, in patients who keep normal serum TSH levels, has been associated with negative skeletal or cardiovascular outcomes.

“However, to our knowledge, not a single study has been published in which T3-containing treatment for hypothyroidism, in patients who keep normal serum TSH levels, has been associated with negative skeletal or cardiovascular outcomes.”

The liver contains sulfatases that can slowly reactivate T3-S via desulfation, secreting T3 back into the circulation.

“Its great advantage lies in the fact that the liver contains sulfatases that can slowly reactivate T3-S via desulfation, “secreting” T3 back into the circulation (59).”

• cites [59] Peeters RP, 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

When tested in vitro, the rate of T3 release from capsules containing modified matrix systems could be modulated according to their content and grade of methyl cellulose and other excipients.

“When tested in vitro, the rate of T3 release from such capsules could be modulated according to their content and grade of methyl cellulose and other excipients (54).”

• cites [54] Bakhteyar H, 2017, Int. J. Pharm. Compd.Not checked — no full text of the source

Similar findings were obtained in Sweden after all-cause mortality was compared between 500,000 patients taking LT4 and 11,000 patients on therapy containing LT3.

“Similar findings were obtained in Sweden after all-cause mortality was compared between 500,000 patients taking LT4 and 11,000 patients on therapy containing LT3 (52).”

• cites [52] sourceNot checked — no full text of the source

T3-S taken orally is readily absorbed into the portal system and the systemic circulation.

“At first, it was thought that T3-S taken orally could not be absorbed through the GI tract, but subsequent studies demonstrated that it is readily absorbed into the portal system and the systemic circulation (58).”

• cites [58] sourceNot checked — no full text of the source

In a recent multicenter prospective randomized controlled trial comparing 141 LT4-treated patients with 143 desiccated-thyroid-extract-treated patients with a mean age of 54 years for almost 1 year, the frequency of adverse events was similar in both parallel arms.

“In a recent multicenter prospective RCT that compared 141 LT4-treated patients with 143 DTE-treated patients with a mean age of 54 years for almost 1 year, the frequency of adverse events was similar in both (parallel) arms (45, 46).”

• cites [45] O'Sullivan A, 2022, ThyroidNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [46] Brazg R, 2022, ThyroidNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

These results illustrate the difficulties in preparing slow-release LT3 formulations while utilizing matrix systems.

“These results are important because they illustrate the difficulties in preparing slow-release LT3 formulations while utilizing matrix systems.”

Engineered chemical conjugates of glucagon and T3 deliver T3 to the liver.

“A unique strategy for directing T3 to the liver included engineered chemical conjugates of glucagon and T3, resulting in the delivery of T3 to the liver (the liver selectively expresses high levels of glucagon receptors) (82).”

• cites [82] sourceNot checked — no full text of the source

• AssumptionRests on an assumption: The liver selectively expresses high levels of glucagon receptors.

In patients with resistance to thyroid hormone, the opposite effect on intrahepatic lipid content is observed.

“Indeed, low-dose LT4 reduces intrahepatic lipid content in patients with type 2 diabetes mellitus and metabolic (dysfunction)-associated fatty liver disease (77), whereas the opposite is observed in patients with resistance to TH (78).”

• cites [78] sourceNot checked — no full text of the source

In some circumstances, reduction in thyroid hormone signaling can be localized to a specific organ.

“While hypothyroidism is a systemic disease, there are circumstances in which a reduction in TH signaling can be localized, restricted to a specific organ.”

In mouse models of obesity, treatment with the glucagon-T3 conjugate corrected hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity.

“Treatment with this conjugate corrected hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in mouse models of obesity.”

• cites [82] sourceNot checked — no full text of the source

Fusing T3 to a second hormone in a single molecular entity can obtain tissue-specific effects of T3.

“These findings support the strategy of fusing T3 to a second hormone in a single molecular entity in order to obtain tissue-specific effects of T3 (82).”

• cites [82] sourceNot checked — no full text of the source

• AssumptionRests on an assumption: The liver selectively expresses high levels of glucagon receptors.

VK2809, a liver-specific THRβ agonist, decreased hepatic triglyceride levels in mice by simultaneous restoration of autophagy, mitochondrial biogenesis, and β-oxidation of fatty acids.

“VK2809, a liver-specific THRβ agonist, decreased hepatic triglyceride levels in mice by simultaneous restoration of autophagy, mitochondrial biogenesis, and β-oxidation of fatty acids (80).”

• cites [80] sourceNot checked — no full text of the source

Low-dose LT4 reduces intrahepatic lipid content in patients with type 2 diabetes mellitus and metabolic (dysfunction)-associated fatty liver disease.

“Indeed, low-dose LT4 reduces intrahepatic lipid content in patients with type 2 diabetes mellitus and metabolic (dysfunction)-associated fatty liver disease (77), whereas the opposite is observed in patients with resistance to TH (78).”

• cites [77] sourceNot checked — no full text of the source

Upon stimulation with TSH, microencapsulated porcine thyroid cells formed 3D follicular spheres that released thyroid hormone.

“Upon stimulation with TSH, these cells formed 3D follicular spheres that released TH (70).”

• cites [70] sourceNot checked — no full text of the source

Thyroid organoids that can be easily transplanted and are capable of restoring thyroid hormone levels in thyroidectomized mice have been developed.

“Thyroid organoids that can be easily transplanted and are capable of restoring TH levels in thyroidectomized mice have also been developed.”

Restoring thyroid hormone signaling in the liver with liver-specific thyromimetic drugs represents a potential therapy for hepatosteatosis in nonalcoholic fatty liver disease.

“Restoring TH signaling in the liver with liver-specific thyromimetic drugs represents a potential therapy for hepatosteatosis in nonalcoholic fatty liver disease.”

• AssumptionRests on an assumption: There are two thyroid hormone receptor genes expressed throughout the body, and the liver predominantly expresses the gene encoding THRβ.

THRβ-selective thyromimetics have reduced effects on the brain and the cardiovascular and musculoskeletal systems compared with THRα effects.

“These molecules have reduced effects on the brain and the cardiovascular and musculoskeletal systems, given their selectivity for the THRβ isoform versus THRα.”

• AssumptionRests on an assumption: There are two thyroid hormone receptor genes expressed throughout the body, and the liver predominantly expresses the gene encoding THRβ.

In a multicenter randomized controlled trial in humans, resmetirom (MGL-3196) decreased hepatic fat content after 12 and 36 weeks.

“Resmetirom (MGL-3196), another liver-specific THRβ agonist, was used in humans for the treatment of NASH in a multicenter RCT; it was found to decrease hepatic fat content after 12 and 36 weeks and could potentially reduce hepatosteatosis and NASH (81).”

• cites [81] sourceNot checked — no full text of the source