Clinical Outcomes After Discontinuation of Thyroid Hormone Replacement: A Systematic Review and Meta-Analysis

Nydia Burgos, Freddy J K Toloza, Naykky M Singh Ospina, Juan P Brito, Ramzi G Salloum, Leslie C Hassett, Spyridoula Maraka, Nydia Burgos, Freddy J K Toloza, Naykky M Singh Ospina, Juan P Brito, Ramzi G Salloum, Leslie C Hassett, Spyridoula Maraka

Abstract

Background: Levothyroxine (LT4) is one of the most commonly prescribed medications. Although considered a life-long replacement therapy, LT4 therapy can be discontinued for some patients. This study aims at: (i) reviewing the evidence on clinical outcomes of patients undergoing thyroid hormone replacement discontinuation, (ii) identifying the predictors of successful discontinuation, and (iii) systematically appraising frameworks used for deprescribing thyroid hormone. Methods: We searched multiple bibliographic databases, including Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus, from inception to February 2020 for studies in which thyroid hormone replacement was discontinued. Clinical outcomes assessed included: proportion of patients that remained euthyroid or needed to restart thyroid hormone replacement after discontinuation and frequency of clinical symptoms of hypothyroidism and adverse effects. We also evaluated predictors for discontinuation and deprescribing frameworks. Reviewers (F.J.K.T., N.B., N.M.S.O., S.M.) evaluated studies for inclusion, extracted data, and assessed methodological quality independently and in duplicate. Results: Seventeen observational studies at moderate to high risk of bias met inclusion criteria, including a total of 1103 patients (86% women) with an age range of 2-81 years. Approximately a third of patients undergoing thyroid hormone discontinuation remained euthyroid at follow-up (37.2%, 95% confidence interval [CI 24.2-50.1%], I2 97.5%). Subgroup analysis showed that patients with a previous diagnosis of overt hypothyroidism (OH) were less likely to remain euthyroid (11.8% [CI 0.4-23.2%], I2 90.3%) than patients with a prior diagnosis of subclinical hypothyroidism (SCH) (35.6% [CI 8.2-62.9%], I2 94.0%). No study followed a framework for systematically deprescribing LT4. Conclusions: Low-quality evidence suggests that up to a third of patients remained euthyroid after thyroid hormone discontinuation, with a higher proportion of patients with an initial diagnosis of SCH remaining euthyroid than patients with an initial diagnosis of OH. A deprescribing framework focusing on adequate selection of patients for deprescribing LT4 and a systematic process is warranted to guide clinicians in re-evaluating the need for LT4 in their patients.

Keywords: deprescribing; levothyroxine; medication withdrawal; subclinical hypothyroidism; thyroid dysfunction.

Conflict of interest statement

The authors have nothing to disclose. No competing financial interests exist.

Figures

FIG. 1.
FIG. 1.
PRISMA flow diagram. PRISMA, Preferred Reporting Items for Systematic reviews and Meta-analysis.
FIG. 2.
FIG. 2.
(A) Percentage of euthyroid adult patients by type of hypothyroidism and follow-up time. 1: Rizzolo et al. (41); 2: Krugman et al. (29); 3: Ohsawa et al.–LT4 arm (30); 4: Ohsawa et al.–LT3 arm (30); 5: Comtois et al. (32); 6: Rieu et al. (33); 7: Livadas et al. (24); 8: Höfling et al. (31); 9: Nikolai (34); 10: Rosario and Calsolari (27). (B) Percentage of euthyroid patients by type of hypothyroidism and follow-up time in studies with mixed patient age groups (children, adolescents, and adults). 1: Battelino (25); 2: Radetti et al. (26); 3: Sklar (37); 4: Wasniewska et al. (36); 5: Fava et al. (38); 6: Takasu et al. (35); 7: Takasu et al. (39). SCH, subclinical hypothyroidism; Overt, overt hypothyroidism.
FIG. 3.
FIG. 3.
Meta-analysis of euthyroidism (%) after thyroid hormone discontinuation, including all studies and subgroup analysis by degree of hypothyroidism and age of participants. CI, 95% confidence interval.
FIG. 4.
FIG. 4.
Meta-analysis of re-initiation of thyroid hormone (% X axis), including all studies and subgroup analysis according to degree of hypothyroidism and age of participants.
FIG. 5.
FIG. 5.
Algorithm for approaching LT4 deprescribing. LT4, levothyroxine; TSH, thyrotropin.

References

    1. Garber JR, Cobin RH, Gharib H. 2013. American Association of Clinical Endocrinologists and American Thyroid Association taskforce on hypothyroidism in adults 2012 clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists a. Endocr Pract 19:175
    1. Fuentes A, Pineda M, Venkata K. 2018. Comprehension of top 200 prescribed drugs in the US as a resource for pharmacy teaching, training and practice. Pharmacy 6:43
    1. Kunsel T, Chandra G 2018 Thyroid Gland Disorder Treatment Market by Disease Type (Hyperthyroidism and Hypothyroidism), Drug Type (Levothyroxine, Liothyronine, Propylthiouracil, Imidazole-based Compound, and Others), Route of Administration (Oral, Intravenous, and Others), and Distribution/Sales Channel (Wholesaler/Distributor, Retailer, Mail-order Pharmacy, and Others)—Global Opportunity Analysis and Industry Forecast, 2017–2025. p 243. Available at (accessed June9, 2020)
    1. Rodriguez-Gutierrez R, Maraka S, Ospina NS, Montori VM, Brito JP. 2017. Levothyroxine overuse: time for an about face? Lancet Diabetes Endocrinol 5:246–248
    1. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. 2000. The colorado thyroid disease prevalence study. Arch Intern Med 160:526–534
    1. Cooper DS, Biondi B. 2012. Subclinical thyroid disease. Lancet 379:1142–1154
    1. Taylor PN, Iqbal A, Minassian C, Sayers A, Draman MS, Greenwood R, et al. . 2014. Falling threshold for treatment of borderline elevated thyrotropin levels—balancing benefits and risks evidence from a large community-based study. JAMA Intern Med 174:32–39
    1. Mooijaart SP, Du Puy RS, Stott DJ, Kearney PM, Rodondi N, Westendorp RGJ, et al. . 2019. Association between levothyroxine treatment and thyroid-related symptoms among adults aged 80 years and older with subclinical hypothyroidism. JAMA 322:1977–1986
    1. Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijaart SP, et al. . 2017. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med 376:2534–2544
    1. Andersen MN, Olsen AMS, Madsen JC, Kristensen SL, Faber J, Torp-Pedersen C, et al. . 2016. Long-term outcome in levothyroxine treated patients with subclinical hypothyroidism and concomitant heart disease. J Clin Endocrinol Metab 101:4170–4177
    1. Grossman A, Feldhamer I, Meyerovitch J. 2018. Treatment with levothyroxin in subclinical hypothyroidism is associated with increased mortality in the elderly. Eur J Intern Med 50:65–68
    1. Lillevang-Johansen M, Abrahamsen B, Jørgensen HL, Brix TH, Hegedüs L. 2018. Over- and under-treatment of hypothyroidism is associated with excess mortality: a register-based cohort study. Thyroid 28:566–574
    1. Thayakaran R, Adderley NJ, Sainsbury C, Torlinska B, Boelaert K, Šumilo D, et al. . 2019. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ 366:1–8
    1. Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P, et al. . 1994. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation. N Engl J Med 221:1249–1252
    1. Somwaru LL, Arnold AM, Joshi N, Fried LP, Cappola AR. 2009. High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over. J Clin Endocrinol Metab 94:1342–1345
    1. Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP. 2010. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab 95:186–193
    1. Bekkering GE, Agoritsas T, Lytvyn L, Heen AF, Feller M, Moutzouri E, et al. . 2019. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ 365:1–9
    1. U.S. Deprescribing Research Network. What is deprescribing?. 2020. Available at (accessed July18, 2020)
    1. Pruskowski J, Handler SM. 2017. The DE-PHARM project: a pharmacist- driven deprescribing initiative in a nursing facility. Consult Pharm 32:468–478
    1. Wouters H, Scheper J, Koning H, Brouwer C, Twisk JW, van der Meer H, et al. . 2017. Discontinuing inappropriate medication use in nursing home residents. Ann Intern Med 167:609–617
    1. Dills H, Shah K, Messinger-Rapport B, Bradford K, Syed Q. 2018. Deprescribing medications for chronic diseases management in primary care settings: a systematic review of randomized controlled trials. J Am Med Dir Assoc 19:923–935.e2.
    1. Moher D, Liberati A, Tetzlaff J, Altman DG. 2009. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62:1006–1012
    1. Wells GS, O'Connell D, Peterson J, Welch V, Losos M. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. Available at (accessed July17, 2020)
    1. Livadas S, Bothou C, Androulakis I, Boniakos A, Angelopoulos N, Duntas L. 2018. Levothyroxine replacement therapy and overuse: a timely diagnostic approach. Thyroid 28:1580–1586
    1. Battelino T, Krzisnik C, Gottschalk ME, Zeller WP. 1994. Testing for thyroid function recovery in children and adolescents with Hashimoto thyroiditis. Ann Clin Lab Sci 24:489–494
    1. Radetti G, Salerno M, Guzzetti C, Cappa M, Corrias A, Cassio A, et al. . 2017. Thyroid function in children and adolescents with Hashimoto's thyroiditis after L-thyroxine discontinuation. Endocr Connect 6:206–212
    1. Rosario PW, Calsolari MR. 2016. Levothyroxine therapy in the subclinical hypothyroidism: a lifelong therapy? A long-term study. Clin Endocrinol (Oxf) 85:819–820
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. 2003. Measuring inconsistency in meta-analyses. BMJ 327:557–560
    1. Krugman LG, Hershman JM, Chopra IJ. 1975. Patterns of recovery of the hypothalamic pituitary thyroid (HPT) axis in patients taken off chronic thyroid therapy. Clin Res 23:70–80
    1. Ohsawa N, Kobayashi I, Suwa K, Kamio N, Maruta S, Ohshima K, et al. . 1981. TSH and prolactin secretions in Hashimoto' s following withdrawal of thyroid hormone thyroiditis therapy. Endocrinol Jpn 28:329–334
    1. Höfling DB, Chavantes MC, Juliano AG, Cerri GG, Knobel M, Yoshimura EM, et al. . 2013. Low-level laser in the treatment of patients with hypothyroidism induced by chronic autoimmune thyroiditis: a randomized, placebo-controlled clinical trial. Lasers Med Sci 28:743–753
    1. Comtois R, Faucher L, Laflèche L. 1995. Outcome of hypothyroidism caused by Hashimoto's thyroiditis. Arch Intern Med 155:1404–1408
    1. Rieu M, Richard A, Sadoudi R, Berrod JL. 1995. Effects of thyroid status on thyroid autoimmunity expression in surgically induced hypothyroid patients with graves' disease. Horm Res Paediatr 44:29–34
    1. Nikolai TF 1989. Recovery of thyroid function in primary hypothyroidism. Am J Med Sci 297:18–21
    1. Takasu N, Yamada T, Takasu M, Komiya I, Nagasawa Y, Asawa T, et al. . 1992. Disappearance of thyrotropin-blocking antibodies and spontaneous recovery from hypothyroidism in autoimmune thyroiditis. N Engl J Med 326:513–518
    1. Wasniewska M, Corrias A, Aversa T, Valenzise M, Mussa A, De Martino L, et al. . 2012. Comparative evaluation of therapy with l-thyroxine versus no treatment in children with idiopathic and mild subclinical hypothyroidism. Horm Res Paediatr 77:376–381
    1. Sklar CA 1986. Juvenile autoimmune thyroiditis. Am J Dis Child 140:877.
    1. Fava A, Oliverio R, Giuliano S, Parlato G, Michniewicz A, Indrieri A, et al. . 2009. Clinical evolution of autoimmune thyroiditis in children and adolescents. Thyroid 19:361–367
    1. Takasu N, Komiya I, Asawa T, Nagasawa Y, Yamada T. 1990. Test for recovery from hypothyroidism during thyroxine therapy in Hashimoto's thyroiditis. Lancet 336:1084–1086
    1. Carlwe M, Schaffer T, Sjöberg S. 2013. Short-term withdrawal of levothyroxine, induced increase of thyroid-stimulating hormone and an increase ratio of triiodothyronine to thyroxine. Eur Endocrinol 9:37–39
    1. Rizzolo PJ, Porr D, Fisher PC. 1986. Reevaluation of patients on thyroxine therapy. J Fam Pract 22:241–244
    1. Pearce SHS, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, et al. . 2013. 2014 ETA guideline: management of Subclinical Hypothyroidism. Eur Thyroid J 2:215–228
    1. Negro R, Attanasio R, Nagy E V., Papini E, Perros P, Hegedüs L. 2020. Use of thyroid hormones in hypothyroid and euthyroid patients; the 2019 Italian survey. Eur Thyroid J 9:25–31
    1. Reeve E, To J, Hendrix I, Shakib S, Roberts MS, Wiese MD. 2013. Patient barriers to and enablers of deprescribing: a systematic review. Drugs Aging 30:793–807
    1. Machado-Alba JE, Gaviria-Mendoza A, Machado-Duque ME, Chica L. 2017. Deprescribing: a new goal focused on the patient. Expert Opin Drug Saf 16:111–112
    1. Reeve E, Gnjidic D, Long J, Hilmer S. 2015. A systematic review of the emerging definition of “deprescribing” with network analysis: implications for future research and clinical practice. Br J Clin Pharmacol 80:1254–1268
    1. Jansen J, Naganathan V, Carter SM, McLachlan AJ, Nickel B, Irwig L, et al. . 2016. Too much medicine in older people? Deprescribing through shared decision making. BMJ 353:1–6
    1. Nixon M, Westendorp RGJ. 2017. When subclinical hypothyroidism becomes clinically diagnosed. Eur J Intern Med 46:34–35
    1. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. . 2014. Guidelines for the treatment of hypothyroidism: prepared by the American thyroid association task force on thyroid hormone replacement. Thyroid 24:1670–1751
    1. Thompson W, Reeve E, Moriarty F, Maclure M, Turner J, Steinman MA, et al. . 2019. Deprescribing: future directions for research. Res Soc Adm Pharm 15:801–805
    1. Reeve E, Thompson W, Farrell B. 2017. Deprescribing: a narrative review of the evidence and practical recommendations for recognizing opportunities and taking action. Eur J Intern Med 38:3–11
    1. Anderson K, Stowasser D, Freeman C, Scott I. 2014. Prescriber barriers and enablers to minimising potentially inappropriate medications in adults: a systematic review and thematic synthesis. BMJ Open 4:e006544
    1. Mauri L, D'Agostino RB. 2017. Challenges in the design and interpretation of noninferiority trials. N Engl J Med 377:1357–1367
    1. Rethlefsen ML, Farrell AM, Osterhaus Trzasko LC, Brigham TJ. 2015. Librarian co-authors correlated with higher quality reported search strategies in general internal medicine systematic reviews. J Clin Epidemiol 68:617–626
    1. Meursinge Reynders R, Ladu L, Di Girolamo N. 2017. Contacting of authors by systematic reviewers: protocol for a cross-sectional study and a survey. Syst Rev 6:249.
    1. Siddaway AP, Wood AM, Hedges LV. 2018. How to do a systematic review: a best practice guide for conducting and reporting narrative reviews, meta-analyses, and meta-syntheses. Annu Rev Psychol 70:747–770

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