Switching from Natural Desiccated Thyroid to a Liquid Formulation of Levothyroxine for Hypothyroidism

Natural desiccated thyroid (NDT) is a treatment option for many patients with hypothyroidism, but some still exhibit symptoms despite achievement of normal levels of thyroid stimulating hormone (TSH). In this retrospective case series, 13 patients with hypothyroid symptoms were switched from NDT to a liquid formulation of levothyroxine (LT4; Tirosint®-SOL). Laboratory values ≥4 weeks following the switch showed a decrease in TSH levels, maintenance of free triiodothyronine (fT3) levels, and significant increases in free thyroxine (fT4) levels. Patients reported good tolerability, and case summaries are presented for four patients. In summary, this small retrospective case series showed that patients who still had hypothyroid symptoms despite use of NDT can respond well to oral LT4 liquid formulation, including patients who are intolerant of gluten and/or lactose or on hormone replacement therapy or iron supplementation.


Introduction
Hypothyroidism results from the defciency of thyroid hormones, specifcally when thyroid stimulating hormone (TSH) levels are elevated and free thyroxine (fT4) levels are reduced compared to reference ranges [1].Te most frequently reported clinical symptoms include fatigue, constipation, weight gain, dry skin, and intolerance to cold temperatures [1,2].Successful treatment of hypothyroidism not only focuses on the reduction of TSH levels but also the need for symptom resolution and improved quality of life (QOL).Administration of levothyroxine (LT4) is the recommended standard of care for the treatment of hypothyroidism according to joint guidelines from the American Tyroid Association and American Association of Clinical Endocrinologists [3,4].
Te use of natural preparations of thyroid hormone was the dominant form of all pharmacological treatment for hypothyroidism until the 1970s [5].Many prescribers still utilize natural desiccated thyroid (NDT) [6,7], derived from porcine thyroid glands, for the treatment of hypothyroidism.While these preparations contain both triiodothyronine (T3) and T4, they are not physiologically equivalent to those seen in humans [8] and possess potential variability in T3 and T4 concentrations [4].Some positive efects of NDT treatment of hypothyroidism have been reported [9,10], but NDT does not always improve QOL compared with LT4 treatment [11].Due to their animal origin, NDT preparations are not an option for vegans, vegetarians, and those who avoid pork for religious reasons.Additionally, NDT preparations have not been widely tested in clinical trials, and as such, they lack evidence of their efcacy versus synthetic LT4.Tere are reports of adverse patient outcomes with compounded thyroid medications due to error [12] and deviations in potency among batches [13,14].Further, a United States Food and Drug Administration (FDA) inspection of the manufacturing facility for WP Tyroid ® and Nature-Troid ® in 2020 found that these products did not conform to standards for strength, purity, or quality [15] and thus were removed from the market.Te FDA has not approved NDT preparations; however, they are regulated by the administration.
A liquid formulation of LT4 is available for the treatment of hypothyroidism.Unlike tablet formulations of levothyroxine and NDT preparations, this LT4 liquid formulation is composed only of levothyroxine, water, and glycerol [16] (Table 1) without other excipients that may interfere with absorption.As such, LT4 liquid formulation exhibits enhanced absorption [17][18][19] with a faster absorption rate [20].In a retrospective study, patients who were switched from LT4 tablets to LT4 liquid formulation achieved a signifcant decrease in TSH levels within 60-90 days [21].Patients treated with LT4 liquid formulation also remained within normal TSH ranges for a longer period of time compared with those on LT4 tablets [22] and exhibited signifcant improvements in QOL as measured on a validated, thyroid-specifc questionnaire [23].
Although there are published reports of switching from LT4 tablets to NDT [9][10][11], to our knowledge, there is no published literature on switching from NDT to LT4 liquid formulation.Tus, this retrospective case series of patients with hypothyroidism evaluated those who had been treated with NDT but still experienced hypothyroid symptoms who were subsequently switched to LT4 liquid formulation.

Methods
Tis was a retrospective analysis of patients with a prior diagnosis or hypothyroidism or Hashimoto's disease who initiated treatment from December 2020 to May 2022 at Natural Endocrinology Specialists PLLC, Scottsdale, AZ, USA.At the initial visit, patients with hypothyroidism exhibited its associated symptoms despite prior treatment with NDT.Patients were switched to individually packaged monodose ampules of LT4 liquid formulation (Tirosint ® - SOL, levothyroxine sodium oral solution, IBSA Pharma Inc., Parsippany, NJ), with the initial dose determined on an individual basis by weight [16] and clinical judgment.LT4 liquid formulation was to be taken upon rising in the morning (between 5:00 and 11:00 am) without food.Two patients were also treated with liothyronine.Data are presented for patients with both pre-switch and post-switch laboratory values for TSH, free T3 (fT3), and free T4 (fT4).Testing was performed by LabCorp or Quest Diagnostics, which utilized the electrochemiluminescence immunoassay for TSH and fT4 and equilibrium dialysis and high-pressure liquid chromatography/tandem mass spectrometry for fT3.Patients were encouraged to use the same testing laboratories for all measurements.LabCorp reference values were used: TSH, 0.45-4.5 μIU/mL [24]; fT3, 2.0-4.4 pg/mL [25]; and fT4, 0.82-1.77ng/dL [26].Retrospective data were verifed by both authors.Data are expressed as medians with interquartile ranges.Te Wilcoxon matched-pairs signed rank test was used in GraphPad Prism (GraphPad Software, San Diego, CA, USA), version 9.4.1, to test for signifcant diferences between pre-switch and post-switch to LT4 liquid formulation.p ≤ 0.05 was considered to be signifcant.Tolerability and adverse events were also noted at every visit.

Patient Demographics.
Tirteen patients were included in this analysis, all female (Table 2; Supplemental Table 1).Eight had a diagnosis of autoimmune thyroiditis (Hashimoto's disease) and fve of hypothyroidism.Five patients had gluten intolerance or celiac disease, with three of those patients also reporting lactose intolerance.Four patients were on hormone replacement therapy.Patients were taking an average of 9 supplements (range 0-18), some of which were multivitamins and iron.Most (12/13) wanted to switch to LT4 liquid formulation because of continued thyroid symptoms despite use of NDT.

Laboratory Measures of Tyroid Function.
Most patients were within the normal TSH range prior to the switch to LT4 liquid formulation (Figure 1(a) and Table 3).Despite these data, they presented with symptoms of hypothyroidism, including fatigue, hair loss, and weight gain (Table 2).Including only the patients receiving LT4 liquid formulation (and not also liothyronine) who had TSH values within or below the normal range, the overall median TSH values decreased from 2.75 μIU/mL prior to the switch to 1.57 μIU/mL ≥ 4 weeks after the switch to individualized doses of LT4 liquid formulation (Figure 1(a)).For all patients, the pre-switch median TSH values were 2.90 μIU/mL, with a post-switch median of 1.89 μIU/mL.For all patients except for the 2 who were also receiving liothyronine, the median TSH values of pre-switch and post-switch were 2.9 and 1.58 μIU/mL, respectively.
Patient K had TSH levels within the normal range before the switch to LT4 liquid formulation 25 μg but levels increased following the switch.Tis patient had also initiated estrogen treatment, which also afected TSH values.Te dosage of LT4 liquid formulation was increased, but no further follow-up data were available for this patient.
Tree patients (A, G, M) had lower than normal TSH values following the switch, and all had their LT4 liquid formulation dosages decreased.Follow-up data were available for one patient (A) after the dose decrease, which showed that this patient still had TSH levels below the normal range at the next assessment, so the dose was further decreased.

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Tree patients (B, F, J) exhibited levels of TSH higher than the upper limit of the normal range of 4.5 μU/mL prior to the switch to LT4 liquid formulation (Table 3).Of these, TSH levels in two of these patients (B, J) decreased to fall within the normal range within ≥4 weeks following the switch.Te third of these patients (F) had abnormally high TSH levels prior to the switch that decreased from 9.82 to 7.40 μIU/mL at day 35 following the switch to LT4 liquid formulation 100 μg and the addition of liothyronine 10 μg.With a dose increase in the LT4 liquid formulation to 112 μg (skipping the dose one day per week) and continuation of liothyronine 10 μg, the patient achieved a TSH level of 2.11 μIU/mL at 40 weeks following the initial switch to LT4 liquid formulation and reported an improvement in her health.
Data for fT3 values for before and after the switch were available for three patients (Figure 1(b)).Prior to the switch, all patients had fT3 values within the normal range (median 2.7 pg/mL), and all maintained normal values following the switch to LT4 liquid formulation (median 2.7 pg/mL).
Seven patients had data for fT4 values before and after the switch to LT4 liquid formulation (Figure 1(c)).Te fT4 values for three patients (E, F, K) were below the normal range, and the other four patients' values were within the normal range prior to the switch.All patients' fT4 values increased with the switch to LT4 liquid formulation, from a median of 0.86 to 1.20 ng/dL, p � 0.0156.Case Reports in Endocrinology

Tolerability and Adverse
Events.For all follow-up visits in which tolerability was recorded, tolerability was described as "good," "great," or "did not notice any diference from NDT." Patient B reported loose stools at the fourth visit (but notably had a history of acute gastroenteritis), when her LT4 liquid formulation dose was decreased (see patient summary below).Patient G, who had a decrease in TSH levels to 0.01 following the switch to LT4 liquid formulation, reported good tolerability but also loose stools on day 67 post-switch.Te dose of LT4 liquid formulation was decreased from 150 to 112 μg, but no further follow-up data were available.

Patient Summaries.
Case summaries are presented for select patients.Patient B was a female, aged 47 years with a BMI of 32.5 kg/m 2 , hypothyroidism, and latent autoimmune diabetes of adults, though she was noncompliant with diabetes medications since they were not covered by her insurance.Te patient reported fatigue and allergies to dairy and gluten.Te patient's initial visit to the clinic was for the reestablishment of care.Te patient was not taking any thyroid medication at the time of the initial visit but had previously taken WP Tyroid and then switched to NP Tyroid 2.5 grain (150 mg).TSH levels were elevated (6.63 μIU/mL) prior to the switch to LT4 liquid formulation 150 μg (once in the morning, 30 minutes away from food) and decreased to 1.91 and 0.801 μIU/mL at 30 and 60 days post-switch, respectively.Te patient maintained fT3 levels within the normal range prior to and 30 days after the switch (both 2.7 pg/mL), and fT4 levels increased from pre-switch to day 30 post-switch, from 0.86 to 1.2 ng/dL.Te patient did not notice any diference in tolerability between NDT and LT4 liquid formulation.At day 59 post-switch, the dose of LT4 liquid formulation was increased to 175 μg but was adjusted back to 150 μg when the patient reported loose stools, gastroenteritis from the prior day, and good tolerability to LT4 liquid formulation at day 80 post-switch.At day 150 post-switch, the patient had TSH levels of 3.44 μIU/mL, no longer had loose stools, and reported a 5-pound weight loss and that she was overall satisfed with her treatment.
Patient D was a female, aged 41 years with a BMI of 17.9 kg/m 2 , on 12 supplements, and with no known allergies at the initial visit.Her reasons for the initial visit were Hashimoto's thyroiditis, general fatigue, and adrenal issues.She reported an inability to gain weight.Te patient had taken compounded thyroid medication but felt horrible, so she switched to NP Tyroid and then to Armour Tyroid.TSH levels prior to the switch to LT4 liquid formulation 125 μg were 3.05 μIU/mL and decreased to 0.853 μIU/mL at day 83 following the switch.She also received intravenous iron due to low (15 ng/mL) ferritin levels.At the sole followup visit after the switch, the patient reported considerable improvement in symptoms and an 8-pound (3.6 kg) weight gain since the frst visit.She expressed satisfaction with her treatment and wished she had started LT4 liquid formulation sooner.
Patient C was a female, aged 64 years with a BMI of 28.9 kg/m 2 , and had a history of autoimmune thyroiditis.She was taking fve supplements as well as hormone replacement therapy for menopause (estradiol, progesterone, and testosterone) and presented with abnormal weight gain, hyperlipidemia, essential fatty acid defciency, and erythrocyte abnormality.Te reason for the initial visit was to reestablish care and receive a yearly physical.Tis patient was taking NP Tyroid 90 mg and was switched to LT4 liquid formulation 150 μg.At day 29 following the switch, TSH levels were 1.91 μIU/mL (from a pre-switch value of 3.0 μIU/mL).Reported tolerability to LT4 liquid formulation was "good" at the visit 57 days post-switch, and the dose was increased to 175 μg.At day 89 post-switch, TSH values were 2.14 μIU/mL, and the patient was tolerating the dose well as reported at the day 98 visit.Te patient maintained fT3 levels within the normal range, with values of 3.0, 2.7, and 2.7 pg/ mL prior to the switch and at days 29 and 89 post-switch, respectively.Tere was an increase in fT4 levels with treatment with LT4 liquid formulation, with 1.1 ng/dL pre-switch, 1.2 ng/dL at day 29 post-switch, and 1.4 ng/dL at day 89 post-switch.
Patient J was a female, aged 65 years, with a BMI of 19.9 kg/m 2 , and had a history of autoimmune thyroiditis.Allergies to gluten and dairy, among others, were reported.Te patient was on 14 supplements and presented with menopause, fatigue, nutritional anemia, hyperlipidemia, osteopenia, migraines, allergies, hair loss, and difculty sleeping.She had taken Armour Tyroid but was unable to tolerate it and so had switched to NP Tyroid.TSH levels were above normal at 8.66 μIU/mL prior to the switch to LT4 liquid formulation 125 μg and decreased to 2.41 μIU/mL 38 days following the switch.Te patient sent a message 5 days following the switch that she was pleased with LT4 liquid formulation.At the visit on day 56 post-switch, the patient reported continued hormonal issues and was receiving testosterone and estradiol injections.Tolerability of LT4 liquid formulation was reported as "good," and the dose was changed at this visit to 125 μg plus 13 μg for a total of 138 μg daily.Since TSH levels decreased to 0.410 μIU/mL at day 104 post-switch, dosing of LT4 liquid formulation was changed to at the next follow-up visit (119 days post-switch) to 125 μg plus 13 μg only on Saturdays and Sundays, with 125 μg on Mondays through Fridays.Tolerability of LT4 liquid formulation was again reported as "good" at this visit.

Discussion
In this retrospective review, most patients had TSH levels within the normal range prior to the switch to LT4 liquid formulation yet remained symptomatic.Here, these patients generally achieved a further decrease in TSH levels following the switch to LT4 liquid formulation.In prior studies, patients with initially normal TSH values who were switched to LT4 liquid formulation from LT4 tablets have also shown signifcant decrease in TSH levels [21,27].

6
Case Reports in Endocrinology Although 0.45-4.5 μIU/mL is the normal range of values for TSH, the optimal upper limit has been proposed to be 2.5 μIU/mL since the TSH levels of >95% of euthyroid individuals are below that value [28].In their clinical experience, the authors have found an optimal TSH range of 1-2.Te median TSH values decreased from 2.75 μIU/mL prior to the switch to 1.57 μIU/mL following the switch to LT4 liquid formulation in patients whose TSH levels were within or below the normal range prior to the switch.
Prior literature has described cases in which comorbid conditions, including lactose intolerance, celiac disease, chronic atrophic gastritis, and bowel resection surgery [29], as well as pregnancy [30], afect the ability to absorb LT4.Several patients (A, B, E, F, J) in this study had intolerances to gluten and/or lactose and had sensitivities to other foods (C, I, L), which are known to decrease the absorption of LT4.Seven of these patients were able to decrease their TSH levels by switching to the LT4 liquid formulation (the eighth patient had TSH levels within the normal range before and after the switch).Notably, three of the patients with gluten and/or lactose intolerance (B, F, J) had elevated pre-switch TSH levels, supporting the idea that they were unable to properly absorb T4.Liquid LT4 has previously ameliorated impaired absorption issues, including in 8 patients with lactose intolerance whose TSH levels normalized when switched from LT4 tablets to LT4 liquid formulation [17].Further, a case study reported that symptoms resolved and TSH levels stabilized in a patient with Hashimoto's thyroiditis and celiac disease following the switch from LT4 tablets to LT4 liquid formulation and a gluten-free diet [31].Another case study found that switching a patient with Hashimoto's disease, gastroparesis, and small intestinal bacterial overgrowth to LT4 liquid formulation from compounded T4/T3 achieved TSH levels within the optimal range with resolution of symptoms [32].
Te concomitant use of certain drugs and supplements, including those containing calcium, iron, biotin, or any multivitamin, can also interfere with the absorption of LT4 [29].In addition to noncompliance with thyroid medication and timing of supplements, a variety of factors can afect the ability to achieve TSH values within the normal range, including the administration of LT4 with food as well as consuming large quantities of fber, papaya, or cofee [29].Cafeine can also afect serum levels of TSH, fT3, and fT4 for several hours following consumption [33].Several patients (A, D, F, I, L) were taking iron supplements or received intravenous iron.Four of these patients exhibited decreases in TSH levels following the switch to LT4 liquid formulation, with the ffth maintaining TSH levels in the normal range, indicating that absorption of LT4 liquid formulation was not afected by the supplemental iron.Previous prospective studies showed decreases in TSH levels following the switch from LT4 tablet to LT4 liquid formulation in patients with hypothyroidism who were also taking iron supplements [34], multiple interfering drugs [18], or proton pump inhibitors [19].Te four patients on hormone replacement therapy in the present study were also able to maintain TSH levels in the normal range.
Tere is no scientifcally validated algorithm to switch patients from LT4 monotherapy to NDT, leading to potential overdosing in some patients.It is noteworthy that in this retrospective analysis, levels of fT3 were maintained within the normal range following the switch from NDT to the monotherapy LT4 liquid formulation.Tese cases demonstrated the ability of the LT4 liquid formulation to maintain normal levels of serum T3, which is of great biological importance [35].In addition, this fnding suggests that conversion of LT4 to LT3 was not an issue for the patients in this study.Only two patients (E, F) in this study received concomitant liothyronine (T3); both had celiac disease and a history of unsuccessful use of NDT and compounded thyroid medication.While NDT preparations contain both T3 and T4, the present study demonstrates that T3 supplementation was not necessary to maintain fT3 levels in most patients receiving LT4 liquid formulation monotherapy.Additionally, none of the patients in this study asked to be prescribed T3 once they had switched to LT4 liquid formulation.As expected, treatment with LT4 liquid formulation resulted in signifcant increases in fT4 levels consistent with previous observations with LT4 liquid formulation compared with LT4 tablets in patients with hypothyroidism [23].Further, the fact that three patients (A, G, M) had lower than normal TSH values following the switch shows that a conservative approach to treatment is best due to the rapid absorption of the LT4 liquid formulation.From a clinical perspective, when switching to LT4 liquid formulation, the availability of a wide range of dosing options helps to prevent overprescribing, development of hyperthyroidism, and adverse efects patients may experience with overtreatment.Furthermore, treating with monotherapy allows the patient to be on the minimal amount medication with the greatest beneft.
Overall analysis of the use of LT4 liquid formulation showed that it was well tolerated by all patients in the study.Patients B and G reported loose stools, a known adverse reaction of overdosage of LT4 [16], following the switch (though patient B reported concomitant gastroenteritis and had diabetes, which is known to cause gastrointestinal issues, including diarrhea [36]).Teir doses of LT4 liquid formulation were subsequently decreased, and patient B reported no loose stools at the next follow-up visit.Additional follow-up data were unavailable for patient G, but both patients reported good tolerability of LT4 liquid formulation.
Te limitations of this study are due to its retrospective nature.Future studies could be prospective with more uniform timing of laboratory assessments and should include a QOL questionnaire to better capture the efects on daily life of LT4 liquid formulation treatment of hypothyroidism.In addition, some patients in this study had their assessments performed at a diferent laboratory and/or at diferent times of day, which may have led to some diferences in laboratory values.
Tis frst-of-its-kind study examined switching from NDT to LT4 liquid formulation, a monotherapy free from excipients, in patients with hypothyroidism.Treatment with LT4 liquid formulation led to maintenance or normalization of laboratory values, resolution of hypothyroid symptoms, Case Reports in Endocrinology and good tolerability.When dose adjustments were required, they were mainly downward titrations, which were most likely needed due to the enhanced absorption of LT4 liquid formulation.No patient switched back to NDT because of worsening symptom control, and all patients were satisfed with treatment.Tese cases demonstrate that LT4 liquid formulation can be part of a treatment plan to holistically address the common issues experienced by patients with hypothyroidism.

Figure 1 :
Figure 1: Box plots of (a) TSH values before and ≥4 weeks after the switch to LT4 liquid formulation for patients with TSH values within or below the normal range (0.45-4.5 μIU/mL) before the switch.(b) fT3 values before and ≥4 weeks after the switch to LT4 liquid formulation for patients who did not also receive liothyronine.Te normal range for fT3 values was considered to be 2.0-4.4 pg/mL.(c) fT4 values before and ≥4 weeks after the switch to LT4 liquid formulation.Te normal range for fT4 values was considered to be 0.82-1.77ng/dL.Median (line within box), frst and third quartiles (top and bottom of box), and minimum and maximum values (whiskers) are indicated.Gray symbols show the individual data points.fT3, free triiodothyronine; fT4, free thyroxine; TSH, thyroid stimulating hormone.

Table 1 :
Excipients in commercially available thyroid treatments.
* In some formulations.2CaseReports in Endocrinology

Table 2 :
Baseline patient demographics and disease characteristics.
N/A, not available.A full list of comorbidities and medications/supplements is available in Supplemental Table1.

Table 3 :
TSH values before the switch and ≥4 weeks after the switch to LT4 liquid formulation for all patients.
Te normal range for TSH values was considered to be 0.45-4.5 μIU/mL.