ABSTRACT
Causes of treatment-refractory hypothyroidism include nonadherence, interference from food or drugs, gastrointestinal disorders, and increased levothyroxine turnover. A practical, stepwise diagnostic approach starts with a detailed history, followed by gastrointestinal and ancillary evaluations. Assay interference and other confounding conditions should also be considered. A trial of levothyroxine formulations other than oral tablets may be useful in select cases.
In treatment-refractory primary hypothyroidism, serum thyroid-stimulating hormone levels stay high even though the patient has been prescribed levothyroxine in supraphysiologic doses (> 1.9 μg/kg/day).
Levothyroxine’s pharmacokinetics are influenced by gastric acidity, intestinal integrity, transporter-mediated absorption, enterohepatic circulation, and drug-drug interactions. However, the primary cause of treatment-refractory hypothyroidism is poor adherence.
A stepwise diagnostic approach starts with a meticulous history followed by gastrointestinal evaluation. Assay interference and confounding disorders should be considered to distinguish true refractoriness from spurious test results.
Correcting factors such as nonadherence, suboptimal dosing schedules, and underlying disorders will generally restore euthyroidism. Alternative levothyroxine formulations may prove useful in some situations.
A 72-year-old woman with primary hypothyroidism is admitted to the hospital with new-onset congestive heart failure. She has been taking levothyroxine for 15 years. Over the past several years, her dose of levothyroxine has been gradually increased to 150 μg/day (equivalent to 3.2 μg/kg/day given her weight of 47 kg) due to elevated thyroid-stimulating hormone (TSH) levels. Her past medical history is also significant for alcohol use disorder with intermittent relapses. Endocrinology was consulted when the patient was found to have a TSH of 64 mIU/L (reference range 0.5–4) and a low free thyroxine (free T4) of 0.5 ng/dL (reference range 0.7–1.8), despite reportedly taking her levothyroxine as instructed. Her last outpatient testing 9 months ago showed a TSH of 52 mIU/L and a free T4 of 0.8 mIU/L.
A CHALLENGE FOR CLINICIANS
Levothyroxine (also called LT4, the “4” referring to the 4 iodine atoms in the molecule) is the first-line treatment for primary hypothyroidism (ie, low serum thyroid hormone levels due to problems in the thyroid gland itself, as opposed to central hypothyroidism, which is due to problems in the pituitary gland, hypothalamus, or both).1,2 It is among the most commonly prescribed medications in the United States.
Adults who have no thyroid gland need T4 replacement in a dose of approximately 1.6 μg/kg body weight/day on the average,1 but the required dose in patients with hypothyroidism varies widely depending on sex, body composition, and the cause of hypothyroidism. Dosing can be adjusted on the basis of serum hormone measures, but multiple population-based studies suggest that only about two-thirds of treated patients have normal TSH levels, the rest having values that are either too high or too low.3
Overtreatment definitely leads to important adverse outcomes such as fractures,4 atrial fibrillation,4 and dementia,5 even at subclinical levels, and thus is of significant clinical concern.
The impact of undertreatment is more controversial, especially concerning subclinical hypothyroidism, since randomized controlled trials in untreated patients with TSH levels that were high but still lower than 10 mIU/L generally have not found treatment to lead to lower rates of cardiovascular disease6 or better quality of life.7 However, large cohort4 and registry studies8 of treated patients do suggest that more profound degrees of undertreatment are associated with adverse effects such as cardiovascular disease, dysrhythmias, fractures, and excess mortality.
Undertreated hypothyroidism represents a unique challenge for clinicians. Raising the levothyroxine dose is generally the first thing clinicians do when patients with primary hypothyroidism continue to have elevated TSH despite treatment. However, a subset of patients have significantly elevated TSH levels despite very high prescribed doses. Patients who do not respond to these high doses can be said to have treatment-refractory hypothyroidism.
Treatment-refractory hypothyroidism has been defined as a persistently elevated serum TSH level despite prescriptions for levothyroxine in high oral doses. While there is no outcomes-based or consensus definition of a high oral dose, the most commonly suggested one is anything higher than 1.9 μg/kg body weight/day.9
Real-world data from Johns Hopkins show that the prevalence of high TSH values is actually higher in patients on higher doses of levothyroxine than lower doses (Figure 1).10 We observed that 5.7% of patients receiving levothyroxine doses higher than 1.9 μg/kg body weight/day (equivalent to > 3.0 μg/kg lean body mass/day) had at least 1 elevated TSH reading, and 3.1% had multiple elevated measures.
Distribution of serum thyroid-stimulating hormone (TSH) measurements by daily levothyroxine dose normalized to lean body mass. Percentile curves (5th–95th) represent the distribution of serum TSH levels (mIU/L) across levothyroxine doses ranging from 0.3 to 4.0 μg/kg lean body mass/day, derived from real-world data in the Johns Hopkins electronic health records. Gray zones indicate high and low reference range for serum TSH. The dashed box highlights the treatment-refractory zone, corresponding to levothyroxine doses of 3.0 μg/kg lean body mass/day or higher (equivalent to the average of 1.9 μg/kg/day actual body weight between men and women); 1.9% of all TSH measurements and 5.7% of treated patients at these doses had elevated TSH values, consistent with levothyroxine-refractory hypothyroidism.10
Used with permission of Mary Ann Liebert, Inc., from Adams R, Mammen JS. Sex differences in risk for iatrogenic thyrotoxicosis among older adults: an analysis from real-world clinical data. Thyroid 2025; 35(5):485–493; permission conveyed through Copyright Clearance Center, Inc.
Defining treatment-refractory central hypothyroidism is more difficult than with primary hypothyroidism, because its target thyroid hormone indices are less well established. We recommend consulting an endocrinologist to manage possible treatment-refractory central hypothyroidism, which we will not discuss further here.
A subset of treated patients achieve biochemical euthyroid goals but nonetheless experience ongoing symptoms. Whether they have treatment resistance or whether the symptoms have an alternative cause remains controversial.11,12 This situation also lies outside the scope of this review, which focuses on high TSH despite high levothyroxine doses.
WHAT HAPPENS TO ORAL LEVOTHYROXINE IN THE BODY?
Treatment-refractory hypothyroidism is largely a problem of delivery, often due to human error, but also due to pharmacokinetics. Oral levothyroxine tablets rely on the coordinated interplay of multiple segments of the gastrointestinal tract for optimal bioavailability.13
In the stomach, sodium levothyroxine tablets dissolve in the acidic gastric juice (pH 1.0–3.0),14,15 which is essential for subsequent absorption. Factors that raise gastric pH such as autoimmune gastritis, Helicobacter pylori infection, or use of proton pump inhibitors interfere with levothyroxine absorption.16
Although controversial, variability in the tablets’ inactive ingredients and manufacturing processes may further influence dissolution kinetics, potentially explaining differences in dissolution profiles of levothyroxine tablets from different sources.17 Newer liquid and softgel preparations, which circumvent the dissolution step, aim for enhanced and therefore more consistent bioavailability.13
In the small intestine, peak absorption of the dissolved levothyroxine occurs within the first 3 hours of ingestion under fasting conditions, with maximal uptake at 1.5 to 2 hours.17 Radioisotope studies have found that about 15% of the dose is absorbed in the duodenum, 30% in the jejunum, and 25% in the ileum.18 The remaining fraction is excreted in the stool. Intestinal absorption depends on mucosal integrity, and conditions such as celiac disease, intestinal parasitosis, or inflammatory enteropathies can significantly impair absorption, even when doses are high.17
For decades, passive diffusion was assumed to be the principal route of intestinal levothyroxine transport, because the molecule is lipophilic. However, a variety of specialized transmembrane transporters such as organic anion-transporting polypeptides and monocarboxylate transporters13 actually account for the bulk of levothyroxine uptake.
In the liver, a fraction of the levothyroxine is extracted before the rest continues to the systemic circulation. Hepatic conjugation—principally glucuronidation and sulfation—enhances solubility and facilitates urinary and biliary excretion of levothyroxine derivatives.
In the gut, these conjugates can subsequently undergo microbial deconjugation, permitting reabsorption of free hormone via enterohepatic recirculation. Disruption of bile secretion, as in cholestatic liver disease or cirrhosis, can impair this recycling pathway and diminish systemic hormone availability.13
In the systemic circulation, levothyroxine is predominantly bound to plasma proteins, including thyroid-binding globulin, with only a small fraction remaining unbound. This free fraction constitutes the biologically available pool, entering target tissues where it undergoes deiodination to the more biologically active form of thyroid hormone, triiodothyronine (T3), a process mediated by type 1 and 2 deiodinases. The liver and kidneys are the major sites of extrathyroidal T3 production. Alternatively, T4 can be converted into reverse T3, an isomer with negligible biological activity, by type 3 deiodinase.13,19
Absorbed levothyroxine is largely eliminated by conjugation into water-soluble metabolites by the liver, which are subsequently excreted in urine or bile. If the glomerular barrier in the kidney is compromised, as occurs in nephrotic syndrome, more protein-bound levothyroxine is eliminated, contributing to faster clearance and increased levothyroxine requirements. Conjugated metabolites that are excreted in bile are eliminated with stool unless recovered by bacterial deconjugation and enterohepatic circulation.
CAUSES OF TREATMENT-REFRACTORY HYPOTHYROIDISM
The causes of treatment-refractory hypothyroidism can be broadly categorized as follows (Table 1):
Errors in drug administration or handling
Gastrointestinal disorders, including decreased gastric acidity and intestinal malabsorption
Conditions that increase hormone requirements or turnover
Drug interactions (Table 2)
Unknown.20
Causes of treatment-refractory hypothyroidism
Select drugs that interfere with oral levothyroxine
However, there are no formal cohort studies or even case series to indicate the prevalences of the various causes.
EVALUATION OF SUSPECTED TREATMENT-REFRACTORY HYPOTHYROIDISM
Although no universally accepted threshold exists, treatment-refractory hypothyroidism may be suspected and an appropriate evaluation started when the levothyroxine dose surpasses expected weight-based requirements in a patient with poorly controlled hypothyroidism as evidenced by a persistently elevated serum TSH.
A levothyroxine dose threshold of 1.9 μg/kg/day is commonly used, which is about 19% above the full replacement dose in young patients without a thyroid gland, as it prompts early evaluation before further levothyroxine dose increases. Interestingly, while this dose is typically assessed relative to total body weight, lean body mass has been shown to better reflect the volume of distribution and therefore correlate with dose requirements. This is relevant in women,21 older adults with autoimmune thyroid disease,22 and people with obesity,23 in all of whom a lower dose per kg body weight is typically more appropriate, sometimes as much as 30% less.
Therefore, a workup for treatment-refractory hypothyroidism might reasonably be initiated earlier in these subpopulations if there is a high clinical suspicion due to persistent TSH elevation with increasing doses. However, the 1.9 μg/kg/day threshold is relatively sensitive and therefore is likely to identify most patients with clinically significant issues. A single out-of-range value should be interpreted in the appropriate clinical context and does not necessarily warrant a workup given the biologic variability that can occur (intercurrent illness, for example).
Once treatment-refractory hypothyroidism is suspected, the first things to ask the patient are when and how they are taking the drug and what else they are ingesting with it, to identify easily reversible causes before proceeding to laboratory testing and other interventions such as evaluation of gastrointestinal disorders that impair levothyroxine absorption.
Assay interference and other reasons for spurious TSH elevation should be considered throughout the evaluation. If a cause cannot be found, referral for levothyroxine absorption testing may be pursued. Figure 2 provides a general framework for the evaluation.
Algorithm for evaluation of treatment-refractory hypothyroidism. The evaluation should follow a minimally invasive approach, starting with history-based inquiries for patient drug administration practices and coingestants to identify easily reversible causes before proceeding to laboratory testing and other interventions for evaluation of gastrointestinal pathologies that impair levothyroxine absorption. In the minority of patients for whom the initial evaluation is nonrevealing, levothyroxine absorption testing in consultation with an endocrinologist may be pursued.
aIn pregnancy, dose increases are appropriate for the condition, given increased physiologic demands.
CBC = complete blood count; IgA = immunoglobulin A; LT4 = levothyroxine; OCs = oral contraceptives; PPIs = proton pump inhibitors; TSH = thyroid-stimulating hormone
History-based evaluation
Most causes of treatment-refractory hypothyroidism can be elucidated through a meticulous history encompassing drug administration and handling practices, medication history, and medical or surgical history (Table 3).
History checklist and patient instructions for treatment-refractory hypothyroidism
Nonadherence, also called “pseudomalabsorption,” is the most common cause of poor hypothyroidism control despite prescription of high-dose levothyroxine. Direct inquiries in a nonaccusatory and nonjudgmental manner are often sufficient to reveal missed doses or challenges with prescription refills. In addition, pill-counting and review of medication-dispensing activity in pharmacies may assist in documenting nonadherence in poor historians or patients who opt not to volunteer their adherence history. Absorption testing (see below) can also be used in this population to demonstrate normal physiology and provide the basis for a plan to obtain control.
It is important to establish a therapeutic alliance grounded in trust to effectively address medication non-adherence, as patients are more inclined to disclose barriers and participate in shared problem-solving when they perceive empathy and understanding from their clinicians.
Interference from food or medications should also be explored with a detailed history in patients with a low suspicion for nonadherence. Medications can reduce levothyroxine absorption through a myriad of mechanisms, most commonly by impairing gastric acidity (eg, proton pump inhibitors) and complexing or sequestrating the hormone (eg, calcium, iron, bile-acid sequestrants) (Table 2).
In treatment-refractory hypothyroidism, levothyroxine should be taken first thing in the morning on an empty stomach, followed by no food for at least 60 minutes after the dose, and spaced appropriately from medications known to interfere with absorption. A key caveat is that adherence is the most important first step, since lack of separation from food can probably be accommodated by reasonable dose increases in most cases,24 and should therefore be instituted only after regular administration has been well established without resolution of hypothyroidism. For medications that can potentially form complexes (eg, calcium, iron), proper spacing (> 4 hours) from levothyroxine avoids this interaction. For others, such as proton pump inhibitors, spacing may be ineffective due to prolonged suppression of gastric acidity by such drugs. Alternative levothyroxine formulations or dose increases can be considered if the proton pump inhibitor cannot be discontinued.
Other medications increase levothyroxine requirements by elevating T4-binding globulin (eg, estrogen-containing contraceptives) or altering levothyroxine metabolism (eg, antiseizure medications, tyrosine kinase inhibitors).25
Product degradation can in rare cases lead to persistent problems and can occur when levothyroxine is past its expiration date or exposed to heat, moisture, or sunlight, as can happen if kept in a transparent bottle or near a window or humidifier.26
Switching between different brands of tablets has not generally been shown to have a major impact on euthyroidism.1,27 However, some patients do not have true treatment resistance but are sensitive to small changes in dose, leading to alternating periods of good control and poor control and subsequent dose changes. In these cases, sticking with a single brand eliminates intermanufacturer variability and can minimize time out of the therapeutic range.
Evaluation for gastrointestinal disorders
The patient’s medical history should be reviewed for gastrointestinal conditions or abdominal surgeries that can impair levothyroxine absorption. Additionally, if gastrointestinal symptoms suggest a gastrointestinal disorder, testing for the relevant condition may be warranted.
Levothyroxine absorption requires both an acidic stomach and an intact intestinal border, mostly in the jejunum and ileum.18 Medical conditions affecting either of these can result in suboptimal response to typical levothyroxine doses (Table 4).
Finding and treating the cause of treatment-refractory hypothyroidism
Gluten and lactose sensitivities can cause gastrointestinal discomfort and malabsorption, and testing for immunoglobulin A tissue transglutaminase or endoscopic evaluation for celiac disease or hydrogen breath testing for lactose intolerance may be warranted. Tablets and gel capsules are available that are free of these ingredients, though insurance coverage varies.
Celiac disease and autoimmune gastritis warrant particular consideration in patients with autoimmune thyroiditis—the most common cause of hypothyroidism—because of their shared autoimmune predisposition.
After bariatric surgery (including sleeve gastrectomy and Roux-en-Y gastric bypass), close monitoring of serum TSH levels is recommended; although levothyroxine requirements mostly decrease with weight loss, up to 15% of patients will need an increase due to malabsorption.28
Helicobacter pylori infection and intestinal parasitosis should also be considered and evaluated in the appropriate clinical context.
Levothyroxine absorption testing
If a detailed history and gastrointestinal evaluation fail to identify a cause for treatment-refractory hypothyroidism, levothyroxine absorption testing can distinguish pseudomalabsorption from true malabsorption. Referral to an endocrinologist is typically appropriate in this setting.
The test involves giving an oral loading dose of levothyroxine under fasting conditions, followed by serial serum T4 measurements.29 Protocols vary, but an oral levothyroxine dose of 1,000 μg is commonly used, with serum free or total T4 measurements typically drawn at hourly intervals over a 4-hour period. Normal absorption in this protocol is defined by either a rise in free T4 greater than 0.40 ng/dL, a peak total T4 greater than 6 μg/dL, or calculated absorption exceeding 60% during the 4-hour period.29
Failure to meet any of the aforementioned end points suggests true malabsorption. Conversely, if the end points are met, pseudomalabsorption (ie, nonadherence) is the likely explanation.
Other considerations
Less commonly, elevations in serum TSH do not reflect poorly controlled hypothyroidism but instead represent false (spurious) elevations due to laboratory artifacts or true elevations secondary to other medical conditions that influence serum TSH levels (Table 5).9,30 Such occurrences complicate the interpretation of thyroid function tests and may falsely suggest treatment-refractory hypothyroidism.
Factors that alter laboratory serum thyroid-stimulating hormone (TSH) measurements
Spurious elevations in TSH may occur due to heterophilic antibodies or rheumatoid factor interfering with the TSH assay. This may be suspected when increasing levothyroxine doses result in increases in serum T4 (and possibly even hyperthyroxinemia) without an accompanying decrease in TSH. Testing at a different laboratory or with a different assay may help resolve this issue, and some laboratories can test directly for antibody interference or perform the assay with dilution.30
Macro-TSH, a biologically inactive complex of TSH and anti-TSH immunoglobulin with decreased clearance, can also lead to elevated serum TSH levels.30
Trough levels. In patients on a once-weekly levothyroxine dosing schedule, testing toward the end of the dosing interval can capture trough-related elevations in TSH. Consistent testing midweek better informs the adequacy of levothyroxine therapy.
Medical conditions that elevate TSH without hypothyroidism include TSH-secreting pituitary adenomas, thyroid hormone resistance, and adrenal insufficiency.9 Such conditions are suspected on the basis of clinical history and laboratory testing, again with high normal or elevated free T4 levels, and levothyroxine therapy would not be appropriate. An endocrinology consultation may be helpful for patients with such discordant thyroid function tests.
Endocrinology referral
While many patients with treatment-refractory hypothyroidism can be effectively managed in primary care, referral to an endocrinologist is appropriate in certain cases. This includes patients with nonrevealing evaluations who are being considered for nonstandard diagnostic or therapeutic strategies such as levothyroxine absorption testing or combination levothyroxine and T3 therapy. An endocrinology referral should also be considered for patients with central hypothyroidism, as well as those with atypical or discordant thyroid function tests (eg, high TSH with an elevated free T4) that require specialist workup for rare causes.
CASE CONTINUED
On examination, our patient’s heart rate is 54 beats per minute, and her skin is dry and coarse. She also appears mildly inattentive. Upon further history-taking, it is noted that the patient fills gaps in recall with inconsistent details and confabulations, consistent with her alcohol use disorder. When her medication routine is examined with this in mind, inconsistencies are apparent and a concern for lack of adherence emerges.
MANAGEMENT
In many cases of treatment-refractory hypothyroidism, a reversible underlying cause can be identified. Table 2 and Table 4 describe interventions according to etiology or interfering drug. A subset of patients may not respond to the initial intervention; the presumed causes should be reviewed and the patient reassessed for other etiologies. Other patients have causes that are more challenging to address (eg, autoimmune gastritis, short bowel syndrome) and leave malabsorption an ongoing concern to which the thyroid hormone dosing needs to be adapted.
Addressing nonadherence
There are many reasons for nonadherence, and discussing a patient’s routine can often yield solutions. Although morning dosing is easiest for most patients, studies suggest bedtime dosing is a reasonable alternative.31
In addition, physicians can take advantage of levothyroxine’s long half-life, as dosing does not need to be daily. Once-weekly administration has been studied in randomized controlled trials and appears to be well tolerated, with only modest differences in TSH and free T4 levels compared with daily dosing and no differences in symptoms.32
Direct observation by family members and pharmacy filling of pill boxes are also helpful adherence strategies.
Of note, serum TSH values may fluctuate depending on how long they are measured after the most recent levothyroxine dose. Specifically, testing performed near the end of a weekly dosing interval may show higher TSH levels, reflecting trough free T4 levels (Table 5). In such patients, testing consistently 1 day after the dose assists in titrating the regimen.
Adjusting levothyroxine dose and routine to avoid interference
Sometimes interference can be managed by adjusting the dosing schedule (Table 2). Specifically, levothyroxine should be separated from calcium and iron supplements by 4 hours, and perhaps longer for bile-acid sequestrants.
Other times we may need to increase the levothyroxine dose, recognizing that it will need to be reduced if the interfering agent is discontinued or changed. This is generally the approach for patients with cancer who are receiving tyrosine kinase inhibitors. The levothyroxine dose is not limited by side effects when the dose is poorly absorbed and thus is not causing signs or symptoms of thyroid hormone excess. Therefore, although it requires multiple tablets, the dose of levothyroxine can be pushed well above the usual weight-based requirement, as long as the increase is ultimately effective.
Trial of alternative levothyroxine formulations
Two alternative oral formulations are available alongside standard levothyroxine tablets: liquid solution and softgel capsules (Table 6). All have comparable bioequivalence in healthy volunteers when taken after prolonged fasting.33 Levothyroxine tablets remain the first-line choice, being widely available and cheaper. However, liquid and softgel formulations may be helpful in some cases in which tablet absorption is impaired by mechanisms that can be circumvented with the liquid and softgel formulations, namely impaired gastric acidity and unavoidable drug or food interference.2
Levothyroxine formulations compared
Liquid levothyroxine (oral solution) is packaged in ampules with predetermined doses that the patient can dilute in water.13 Unlike levothyroxine tablets, liquid levothyroxine does not require dissolution in the stomach and therefore does not depend on gastric acidity. Thus, it has shown benefit in patients on proton pump inhibitors.34
Liquid levothyroxine is also absorbed faster, allowing for shorter separation intervals from food and beverages, which can increase convenience such as when giving it to patients receiving nutrition through a gastrostomy tube, as it obviates the need for long feeding interruptions.13 Other potential recipients are those with difficulty swallowing tablets, such as pediatric patients. Nevertheless, this formulation is limited by availability, cost, and an unpleasant taste.
Softgel levothyroxine consists of levothyroxine dissolved in glycerol contained within a gelatin shell. The shell protects the levothyroxine from immediate mixing with food particles. Like liquid levothyroxine, softgel levothyroxine does not require gastric acidity to dissolve, but it is much better tolerated. In many, but not all, patients it is better absorbed than tablets. An open-label study in patients on proton pump inhibitors showed improved TSH levels and lower doses.35 The formulation also has equivalent absorption when taken with coffee or food, which may improve levels in patients who find it difficult to fast after taking their levothyroxine owing to their daily routines.36
Clinicians should be cautious when switching formulations in elderly patients or those with cardiovascular diseases, who are particularly susceptible to thyrotoxicosis, which could be induced by any enhanced absorption. A dose reduction to account for the anticipated improvement in absorption may be appropriate in these patients. Some trials reduced the dose when switching to a liquid or softgel capsule formulation.37
Parenteral levothyroxine is very expensive, limiting its use to urgent and emergent situations. Intravenous levothyroxine is appropriate in cases of severe hypothyroidism presenting with myxedema coma. In such cases, it is administered as a loading dose followed by maintenance doses that are 70% to 80% of an appropriate weight-based oral dose, given complete bioavailability through the intravenous route, until the patient can be transitioned to oral therapy.13
Clinicians have reported giving levothyroxine intramuscularly and subcutaneously in cases of severe gastrointestinal malabsorption that could not be overcome by increased oral intake or alternative oral formulations, such as short gut syndrome, bariatric surgery, or unexplained severe levothyroxine malabsorption.17,38–40
Liothyronine monotherapy and levothyroxine-liothyronine combination therapy
Liothyronine can be given alone or in combination with levothyroxine as thyroid hormone replacement therapy. Compared with levothyroxine, liothyronine (synthetic T3) is absorbed more rapidly, with peak serum concentrations usually occurring about 1 to 2.5 hours after ingestion, and has much higher bioavailability (reaching 95%, vs 60% to 80% for levothyroxine).41,42
Although T3 and T4 use overlapping transporter systems in various body tissues, they differ in substrate specificity. T3 is mostly transported by monocarboxylate transporters 8 and 10, whereas organic anion-transporting polypeptides dominate T4 transport, supplemented by lower-affinity transport through monocarboxylate transporter 8.43
Because liothyronine has a much shorter half-life than levothyroxine (generally about 18–22 hours vs about 6–7 days for levothyroxine), its levels decline more quickly,41 producing higher peaks and lower troughs unless multiple daily doses or modified formulations are used. Pharmacokinetic studies demonstrate that the short half-life of liothyronine requires every-8-hour doses for oral administration to achieve steady state levels,41,44 which limits its practical viability as monotherapy.
However, combination therapy is available, including desiccated pig thyroid preparations that have been in use since the 19th century and can still be prescribed today, and approaches with liothyronine tablets taken in combination with levothyroxine more closely approximate human thyroid production. Long-acting (slow-release) liothyronine formulations are also being developed that might improve the delivery of this alternative.
The best clinical uses for these combinations remain a topic of conversation,44,45 given the possible difficulties in achieving a euthyroid state. However, in view of the differences in absorption and transport, combination therapy may be an interesting option for patients with treatment-refractory hypothyroidism in whom other strategies have not been successful.
Currently, combination therapy is not routinely prescribed and is not available in formulations that match the human thyroid’s secretion ratios; hence, dosing and titration can be challenging. Moreover, no consensus guidelines on its use are available. Therefore, the decision to start combination levothyroxine-liothyronine therapy and the appropriate dosing should be individualized and made in consultation with an endocrinologist.
CASE CONCLUDED
Our patient’s niece, who provides some care for her, offers to come over 3 days a week to administer her levothyroxine. The patient is transitioned to supervised intermittent dosing: levothyroxine 125 μg 3 times weekly (about 1.1 μg/kg/day) under her niece’s supervision. Eight weeks later, the patient’s TSH has normalized to 3 mIU/L, with clinical improvement.
MOST CASES ARE MANAGEABLE
In most instances, treatment-refractory hypothyroidism conceals a remediable cause rather than representing a true pharmacologic impasse. Attention to regular administration, gastrointestinal comorbidities, and interfering drugs or foods often unveils correctable factors that, if addressed, can restore biochemical euthyroidism.
A systematic approach can avert the cascade of unnecessary dose escalations and laboratory testing and the morbidity of persistent hypothyroidism. Moreover, the growing availability of alternative levothyroxine formulations, including liquid and softgel formulations, provides clinicians with additional tools to overcome specific causes of levothyroxine malabsorption. With shared decision-making and patient-centered care, most cases of treatment-refractory hypothyroidism are ultimately manageable.
DISCLOSURES
Dr. Mammen has disclosed consulting for Amgen and research as a principal investigator for Interpace Diagnostics. Dr. Sweis reports no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
Acknowledgments
The authors thank Roy Adams, MS, PhD, for his assistance in adapting Figure 1 for this review.
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