5 clinical pearls for optimizing levothyroxine therapy

Thyroid disease is one of the most underdiagnosed health conditions around the world.1 In Canada, it is estimated that about one in 10 people have some type of thyroid condition, but as many as 50% are undiagnosed.2 Hypothyroidism is the most common thyroid disorder, affecting about five in 100 individuals; if misdiagnosed or untreated, the consequences can have significant and long-term health impacts.1,3,4 For anyone diagnosed with hypothyroidism, thyroid hormone replacement with levothyroxine is recognized as the first-line treatment option.4,5Pharmacists can play an important role in screening patients for hypothyroidism through early recognition of the common signs and symptoms. By identifying patients that may warrant further investigation and referring accordingly, pharmacists can help decrease the rate of missed diagnosis and facilitate timely access to treatment. Pharmacists are also ideally situated to assess for medication nonresponse and can educate on common drug and food interactions that may interfere with levothyroxine absorption and therapeutic effect. Furthermore, as the role of pharmacists in Canada continues to grow and expand, pharmacists should gain confidence in understanding and interpreting basic blood work to make recommendations on medication dose adjustments.These five tips can help pharmacists gain confidence in optimizing levothyroxine therapy.Recognize the common signs and symptoms of hypothyroidism—diagnosis is easily missedHypothyroidism can be thought of as the body’s engine “slowing down.” As a result, the most common signs and symptoms include fatigue, weight gain, sensitivity to cold, voice changes, poor appetite, dry and coarse skin, brittle hair or nails, constipation, menstrual cycle irregularities, depression and poor concentration.3-5 In more serious cases, these symptoms may be accompanied by a decrease in the patient’s mental status, decrease in body temperature, and decreases in blood pressure, heart rate and/or respiration rate.3-5 The opposite is true for patients who may be overtreated; they may experience signs of hyperthyroidism, such as weight loss, heat intolerance, tremor and palpitations, which have been reported in more than 20% of those treated with a thyroid hormone.5,6Gain confidence in understanding thyroid function testsThree main tests are ordered for patients with hypothyroidism: thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3).5,6 TSH is the main hormone released by the pituitary gland, in response to the needs of the body; it signals the pituitary gland to produce thyroid hormones as needed (Figure 1).7 FT4 and FT3 are the two main hormones released by the thyroid gland and collectively make up the “thyroid hormones.”7 In the setting of hypothyroidism, the thyroid gland fails to produce sufficient amounts of FT4 and FT3 and supplementation with synthetic thyroid hormones, such as levothyroxine, is required to restore optimal function of this pathway (Figure 2).3,5,7In the general adult population (excluding pregnant women and older people), a normal TSH level is defined as 0.45–4.50 mIU/L and values > 10 mIU/L are generally indicative of patients that would benefit from levothyroxine treatment.5,6,8,9 TSH is the most sensitive and specific test for the investigation and management of hypothyroidism.5,6 TSH elevations beyond 4.50 mIU/L (but < 10 mIU/L) with low FT4 level values may also be indicative of hypothyroidism; however, FT4 and FT3 alone should not be used to diagnose hypothyroidism or to make levothyroxine dose adjustments in patients with hypothyroidism.5,8,10Be patient in monitoring and testingIt is recommended to wait at least six to eight weeks after initiating levothyroxine therapy, or after every dose adjustment, before rechecking the TSH level.5,6 In most people, once the TSH level is stable and within normal limits, it indicates an adequate levothyroxine replacement dose and additional testing every 12 months is considered acceptable.5,6,8 If testing reveals an abnormal result, then more frequent monitoring is recommended together with medication dose adjustments as needed, until the TSH stabilizes in the normal range.5,6 However, when interpreting thyroid function tests, it is important to correlate what happened with the patient during the last eight weeks and rule out nonadherence (i.e., missed doses), malabsorption and drug interactions. More frequent monitoring may also be needed in special circumstances such as pregnancy, major weight change or initiation of new medications that may interact.9 If you ever notice that the TSH level remains out of range, despite corrected levels of FT4 or FT3, the patient would warrant further investigation for conditions such as pituitary or hypothalamic disease.5,10Recommend a regimen for optimal adherence and absorption in newly diagnosed patientsIdeally, levothyroxine should be taken on an empty stomach with water, at a consistent time each day.11 Acidity in the stomach has been suspected to increase absorption, while high gastric pH (low acidity) may decrease absorption.12 This is why it is important to educate patients to take levothyroxine at least 30 minutes before breakfast or a minimum of three hours after dinner (e.g., at bedtime), and avoid co-administration with antacids or proton pump inhibitors (PPIs).5,11 Levothyroxine should also be spaced from any supplements containing iron or calcium, or bile acid sequestrants (i.e., cholestyramine, colesevelam, colestipol), by at least four hours as these products are known to decrease levothyroxine absorption.5,11Ensure consistency in levothyroxine administration in stable patients on long-term therapyDespite the aforementioned recommendations for optimal drug absorption, in patients taking levothyroxine on an alternate schedule, for example with food or only one hour apart from iron- or calcium-containing supplements, but their TSH is within normal levels, changing their administration regimen is not recommended.9 By that point in the patient’s treatment journey, the dose has likely been adjusted (i.e., increased) to account for the possible interactions that may be interfering with absorption. Recommending changes that may increase medication absorption in a patient that has achieved normal thyroid levels will likely destabilize hormone levels and lead to unnecessary testing, monitoring and dose adjustments.SummaryHypothyroidism is a common but underdiagnosed medical condition. Pharmacists can play an important role in screening, treatment and long-term management. Levothyroxine is the first-line treatment option for hypothyroidism, but requires monitoring and possible dose adjustments. While commonly known products, such as antacids, PPIs, bile acid sequestrants, iron and calcium, interact with levothyroxine, pharmacists should still do a diligent review of all the patient’s medications and supplements to check for possible interactions. Meanwhile, those on long-term therapy with stable blood work should be encouraged to continue their regimen without adjustments.Nicole Domanski (nicole.domanski@ubc.ca) is a clinical pharmacist at the Pharmacists Clinic and lecturer within the Faculty of Pharmaceutical Sciences, both located at the University of British Columbia, Vancouver campus, which is the traditional, ancestral, unceded territory of the speaking (Musqueam people).References:Stoll K. Disparities in thyroid screening and medication use in Quebec, Canada. Health Equity 2019;3(1):328-35. doi:10.1089/heq.2018.0051.Thyroid Foundation Of Canada. Hypothyroidism. (accessed June 6, 2024).Thyroid Foundation Of Canada. About thyroid disease. (accessed June 6, 2024).Chaker L, Bianco AC, Jonklaas J, et al. Hypothyroidism. Lancet 2017;390:1550-62. doi:10.1016/S0140-6736(17)30703-1.Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract 2012;18(6):988-1028. doi:10.4158/EP12280.GL.Toward Optimized Practice Endocrine Working Group. Investigation and management of primary thyroid dysfunction clinical practice guideline. April 2014; Edmonton, AB. (accessed June 8, 2024).Cleveland Clinic. Thyroid hormone: what it is & function. (accessed June 7, 2024).Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid 2014;24(12):1670-751. doi:10.1089/thy.2014.0028.Sawka AM, Jonklaas J. Hypothyroidism. CMAJ 2015Canadian Society of Endocrinology and Metabolism. Five things physicians and patients should question. Choosing Wisely Canada; 2014. (accessed June 7, 2024).Eghtedari B, Correa R. Levothyroxine. Updated August 28, 2023. In: StatPearls [Internet]; Treasure Island, FL: StatPearls Publishing. (accessed July 11, 2024).Ianiro G, Mangiola F, Di Rienzo TA, et al. Levothyroxine absorption in health and disease, and new therapeutic perspectives. Eur Rev Med Pharmacol Sci 2014;18(4):451-6.

5 clinical pearls for optimizing levothyroxine therapy

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