Biomedical Research

Abstract

Objectives: The aim of the present study was to investigate the misuse of levothyroxine treatment in patients with hypothyroidism.

Methods: Patients who received levothyroxine treatment were included in the study. Age, gender, duration of medication use, Thyrotropin (TSH) level, regular use of medication, time and manner of taking medication, drug storage conditions and use of additional medication were recorded. Taking the medication on a full stomach or in the evening, occasional use of medication, storing the medicine in the refrigerator, and the use of additional medication were classified as misuse of levothyroxine treatment. According to the levels of TSH: 0.4-4.5 mIU/L was considered a normal dose, while 4.5 mIU/L and above was considered insufficient, and 0.4 mIU/L and below was considered as high dose.

Results: Patients who received levothyroxine pill were included in the study (average age: 53 ± 14 years, average duration of medication use: 48 ± 50 months and females/male ratio: 363/44). 323 (79.4%) of patients stated that they take the medicine regularly. Levothyroxine dosage was found to be sufficient in 235 patients (57.7%), insufficient in 101 patients (24.8%) and high in 71 patients (17.4%). Among the 84 patients which were identified as misusing, 66 (16.2%) patients were taking the medicine on a full stomach, 12 (2.9%) patients were taking the medicine in the evening, 11 patients (2.7%) were storing the medicine in the refrigerator, 17 (4.2%) patients were taking the medicine occasionally, and 21 (5.1%) patients were using one or more additional medications.

Conclusions: Taking the medication on a full stomach or in the evening, occasional use of medication, storing the medicine in the refrigerator, and the use of additional medications were the major factors for insufficient TSH levels. Appropriate usage of levothyroxine pills is crucial for successful treatment.

Keywords

Levothyroxine treatment, Rate of achieving target thyroid-stimulating hormone, Misuse of levothyroxine.

Introduction

Levothyroxine is used in the treatment of low or insufficient thyroid hormones [1]. Levothyroxine should be taken as a single dose with water on an empty stomach at least 30 min before eating in the morning, and should not be taken with another medication [2,3]. As levothyroxine preparations may not have the same therapeutic efficacy at the same doses, treatment should be maintained with identical preparations. Thyroid hormone absorption can be affected by age, celiac disease, malabsorption, and Proton Pump Inhibitors (PPI), as levothyroxine preparations are dissolved in an acidic environment [4]. Drug interactions with iron preparations, antacids such as aluminium hydroxide, cholestyramine, sucralfate, and calcium may affect the absorption of levothyroxine [5-7]. These types of drugs should be taken at least 4 hours after levothyroxine administration.

Some sources state that levothyroxine tablets can be taken in the evening [8,9]. However, levothyroxine is most often administered in the morning, on an empty stomach, in order to increase its oral absorption [2,3,9-11].

Up to 80% of levothyroxine taken orally is absorbed by the upper part of the small intestine. Effects begin 3-5 days after oral intake. The average half-life of levothyroxine is 7 days. Levothyroxine preparations should be protected from light and stored at room temperature (below 25°C) [12].

According to the levels of TSH: 0.4-4.5 mIU/L was considered a normal dose, while 4.5 mIU/L and above was considered insufficient, and 0.4 mIU/L and below was considered as high dose [9,13].

Taking the medication on a full stomach or in the evening, only occasional use, storage in the refrigerator and the use of additional medication are common types of misuse of the levothyroxine treatment. There are few studies in the literature on the misuse of levothyroxine [14,15].

Many studies have shown that taking levothyroxine on an empty or full stomach. Gastric acidity and drug interactions affect plasma levels of levothyroxine, but the proportion of the patients is affected by this condition in clinical practice has not been investigated until now. Moreover, during evaluation of thyroid function tests which are not in a normal range, mistakes associated with levothyroxine use are usually not considered by physicians [15]. In our study, we aimed to investigate the common mistakes of patients using levothyroxine treatment.

Subjects and Methods

A total of 407 patients who received levothyroxine pills were included in the study. Institutional Ethics permission was obtained from the Rize Findikli Goiter Research and Treatment State Hospital in Turkey in 25-November-2014 (approval number: 2417/2014). Age, gender, duration of medication use, TSH level, indications for use, regular use of medication, time and manner of taking medication (on a full/empty stomach, morning and evening, occasionally), drug storage conditions (storing in refrigerator), use of supplementary medications (iron, Proton Pump Inhibitor (PPI), antacid, etc.), and drug dosage information were recorded. Taking the medication on a full stomach or in the evening, occasional use of medication, storing the medicine in the refrigerator, and the use of additional medication were classified as misuse. In the treatment of levothyroxine, TSH levels of 0.4-4.5 mIU/L were considered a normal, 4.5 mIU/L and above as insufficient and 0.4 mIU/L and below as a high dose.

Patients aged 15 years and above receiving levothyroxine treatment due to hypothyroidism or operated goitre and patients receiving levothyroxine treatment for at least 6 months were included in the study. Patients undergoing levothyroxine treatment for less than 6 months, patients with thyroid cancer or central hypothyroidism, and patients with gastrointestinal disease were excluded from the study.

Statistical analysis

Statistical analysis was performed using the SPSS 18.0 software program. Categorical variables were expressed in numbers or percentages, and the continuous variables were expressed by mean ± standard deviation. Categorical variables were compared using the Chi-square test. For continuous variables, the Kolmogorov-Smirnov test was used first to test the normal distribution of the parameters. The independent samples t-test was used to compare data for normal distribution. A probability value of p<0.05 was considered statistically significant.

Results

A total of 407 patients receiving levothyroxine were included in this study (average age: 53 ± 14 years; average duration of medication use: 48 ± 50 months; female/male ratio: 363/44). 323 (79.4%) patients stated that they take the medicine regularly. Levothyroxine dosage was found to be sufficient in 235 patients (57.7%), insufficient in 101 patients (24.8%) and high in 71 patients (17.4%). Among the 84 patients identified as misusing, 66 (16.2%) patients were taking the medicine on a full stomach, 12 (2.9%) patients were taking the medicine in the evening, 11 patients (2.7%) were storing the medicine in the refrigerator, 17 (4.2%) patients were taking the medicine only occasionally, and 21 (5.1%) patients were using one or more additional medications.

Fifty-one (77.3%) patients who received levothyroxine treatment on a full stomach had higher level of TSH, while 11 (16.7%) had normal levels and 4 (6.1%) had lower levels of TSH. The level of TSH was found to be insufficient in 16 (94.1%) patients skipping levothyroxine pills occasionally, whereas TSH levels were higher in 11 (100%) patients storing levothyroxine preparation in the refrigerator, and TSH levels were found to be higher in 15 (71.4%) patients taking additional medication. The majority of the patients were female. No statistically significant differences were found between males and females in terms of rate of achieving target TSH level, average age, duration of drug use, indications for use, rate of regular use and misuse rates.

Results are summarized in Tables 1 and 2.

Table 1. Characteristics of patients according to TSH levels.

Table 2. Analysis of the patients according to gender.

Discussion

In the literature, few studies have examined the misuse of levothyroxine treatment and rates of achieving target TSH levels. Similarly, few studies have been conducted on genderbased differences in levothyroxine misuse. Thus we aimed to investigate the characteristics of the levothyroxine misuse in terms of the rate of the achieving target TSH levels and genderbased differences.

In a multi-centered study conducted on the patients with hypothyroidism receiving levothyroxine treatment in India, abnormal TSH levels were found in 1051 (54.6%) patients and the levels of TSH was above 4.0 mIU/L in 808 (41.97%) patients, and below 0.4 mIU/L in 243 (12.62%) patients [14]. No data regarding levothyroxine misuse was provided in that study. In a study conducted on patients with hypothyroidism receiving levothyroxine treatment, the TSH levels were found to be normal range in 74% of the patients; TSH levels were high in 17.5% of patients and low in 8.5% of patients [15]. In that study, taking medication on a full stomach, storing in the refrigerator, and taking additional medication were considered major misuse of medication [15].

In a study conducted on patients with hypothyroidism secondary to thyroidectomy, TSH levels were normal in 59% of the patients, TSH levels were suppressed in 23% of the patients and TSH levels high in 18% of the patients [16]. Similarly, in our study, TSH levels were found to be normal in 59% of the patients taking levothyroxine for those with hypothyroidism secondary to thyroidectomy.

Taking levothyroxine pill on a full stomach will require higher doses of levothyroxine compared to taking it on an empty stomach to achieve the target level of TSH [17]. In the present study, TSH was found to be high in 77.3% of the patients who took levothyroxine on a full stomach.

Levothyroxine dosage usually is 1.6 μg/kg body weight, which is 100 to 150 μg/kg for men and 75 to 100 μg/kg for women [18]. The aim of the treatment is to normalize the serum TSH levels [19]. Thyroid hormones can also directly modulate circulation and peripheral vascular beds. So that levothyroxine sufficient dosage was very important [20]. The higher TSH levels demonstrate insufficient dosage of the levothyroxine treatment, the lower TSH levels demonstrate over-dosage of the levothyroxine treatment and normal TSH levels show sufficient dosage of the levothyroxine treatment. In the present study levothyroxine dosage was found sufficient in 235 (57.7%) patients, insufficient in 101 (24.8%) patients, and high in 71 (17.4%) patients.

One or more misuse of levothyroxine pills was detected in 84 patients in the present study. For the most common misuse of levothyroxine pills, 66 (16.2%) patients were taking the pills on a full stomach, 12 (2.9%) patients were taking the pills in the evening, 11 patients (2.7%) stored the pills in the refrigerator, 17 (4.2%) patients were taking the pills occasionally, and 20 (4.9%) patients were using one or more additional pills.

We also investigated gender in terms of achieving the target TSH level. The ratio of the achieving the target TSH level was found 45.5% in males and 59.0% in females. No statistically significant differences were found between genders in terms of the investigated parameters.

Conclusion

In the present study, we demonstrated that the rate of the achieving target level of TSH was 57.7%. Medication misuse was found in 20.6% of the patients. Major factors for insufficient values of TSH levels include taking medication on a full stomach or in the evening, occasional use of medication, storing the medicine in the refrigerator, and the use of additional medication. Patients should be made aware of proper storage and use of levothyroxine pills, as these are crucial for successful treatment.

Financial Support and Sponsorship

Nil

Conflict of Interest

There is no conflict of interest

References

1. Vaidya B, Pearce SH. Management of hypothyroidism in adults. BMJ 2008; 337: a801.
2. Perez CL, Araki FS, Graf H, de Carvalho GA. Serum thyrotropin levels following levothyroxine administration at breakfast. Thyroid 2013; 23: 779-784.
3. Bolk N, Visser TJ, Kalsbeek A, van Domburg RT, Berghout A. Effects of evening vs. morning thyroxine ingestion on serum thyroid hormone profiles in hypothyroid patients. Clin Endocrinol (Oxf) 2007; 66: 43-48.
4. Ianiro G, Mangiola F, Di Rienzo TA, Bibbo S, Franceschi F. Levothyroxine absorption in health and disease, and new therapeutic perspectives. Eur Rev Med Pharmacol Sci 2014; 18: 451-456.
5. Trifiro G, Parrino F, Sultana J, Giorgianni F, Ferrajolo C, Bianchini E. Drug interactions with levothyroxine therapy in patients with hypothyroidism: observational study in general practice. Clin Drug Investig 2015; 35: 187-195.
6. Campbell NR, Hasinoff BB. Iron supplements: a common cause of drug interactions. Br J Clin Pharmacol 1991; 31: 251-255.
7. Ward LS. The difficult patient: drug interaction and the influence of concomitant diseases on the treatment of hypothyroidism. Arq Bras Endocrinol Metabol 2010; 54: 435-442.
8. Bolk N, Visser TJ, Nijman J, Jongste IJ, Tijssen JG. Effects of evening vs. morning levothyroxine intake: a randomized double-blind crossover trial. Arch Intern Med 2010; 170: 1996-2003.
9. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS. American Thyroid Association Task Force on Thyroid Hormone Replacement. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid 2014; 24: 1670-1751.
10. Ala S, Akha O, Kashi Z, Bahar A, Askari Rad H, Sasanpour N. Changes in serum TSH and T4 levels after switching the levothyroxine administration time from before breakfast to before dinner. Int J Endocrinol 2015; 2015: 156375.
11. Ala S, Akha O, Kashi Z, Asgari H, Bahar A, Sasanpour N. Dose administration time from before breakfast to before dinner affect thyroid hormone levels? Caspian J Intern Med 2015; 6: 134-140.
12. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI. American Association of Clinical Endocrinologists and American Thyroid Association Task force on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocr Pract 2012; 18: 988-1028.
13. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA. Serum TSH, T(4),and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002; 87: 489-499.
14. Mithal A, Dharmalingam M, Tewari N. Are patients with primary hypothyroidism in India receiving appropriate thyroxine replacement? An observational study. Indian J Endocr Metab 2014; 18: 83-88.
15. Kucukler FK, Akbaba G, Arduc A, Simsek Y, Guler S. Evaluation of the common mistakes made by patients in the use of Levothyroxine. Eur J Intern Med 2014; 25: e107-108.
16. Jin J, Allemang MT, McHenry CR. Levothyroxine replacement dosage determination after thyroidectomy. Am J Surg 2013; 205: 360-363.
17. Bach-Huynh TG, Nayak B, Loh J, Soldin S, Jonklaas J. Timing of levothyroxine administration affects serum thyrotropin concentration. J Clin Endocrinol Metab 2009; 94: 3905-3912.
18. Mandel SJ, Brent GA, Larsen PR. Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 1993; 119: 492-502.
19. Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am 2012; 96: 203-221.
20. Scicchitano P, Dentamaro I, Tunzi F, Ricci G, Carbonara S. Pulmonary hypertension in thyroid diseases. Endocrine 2016.