Refractory hypothyroidism due to improper storage of levothyroxine tablets
Open accessAbstract
CONTEXT: A not negligible part of hypothyroid patients on levothyroxine therapy do not normalize serum thyrotropin (TSH) concentrations. "Refractory hypothyroidism," i.e., a condition characterized by persistently abnormal serum TSH levels despite adequate titration of l-T4 substitution therapy, requires biochemical and instrumental investigation, but no definite etiology is found in up to 15% of cases. OBJECTIVE: To report patients presenting with refractory hypothyroidism with proven improper storage of levothyroxine tablets. DESIGN: Patients on l-T4 substitution therapy referred to three Italian outpatient Clinics of Endocrinology between January 2013 and December 2015 for refractory hypothyroidism were investigated for levothyroxine tablet exposure to humidity, light, and high temperature. RESULTS: We report eight patients, accounting for approximately 1% of all hypothyroid patients and 5% of those with refractory hypothyroidism in our series. Careful anamnesis disclosed that these patients stored levothyroxine tablets inappropriately. Normalization of serum TSH concentrations was obtained in all cases by simply recommending to store the new levothyroxine tablets away from heat, light, and humidity. CONCLUSION: Refractory hypothyroidism linked to improper storage of l-T4 tablets does exist and might be an underrecognized entity. In addition to proper modalities of ingestion of l-T4 tablets, patients need to be instructed on proper modalities of storage, as well.
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A case series reported clinical evidence of refractoriness of hypothyroidism due to improper storage of tablet levothyroxine.
“A case series article reported some clinical evidence of the refractoriness of hypothyroidism due to improper storage of tablet levothyroxine (27).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [27]
More than 15% of levothyroxine-treated patients fail to achieve the recommended serum TSH level.
“Despite a daily levothyroxine dose of more than 1.9 µg/kg/day, between 15% and 20% of levothyroxine-treated patients present hypothyroid symptoms or have TSH levels above the upper limit of the reference range [3, 4].”
From Levothyroxine Absorption Test With the Daily Levothyroxine Dose in Patients With “Refractory Hypothyroidism” (2025) · cites this paper as [4]
Blister packaging may eliminate refractory hypothyroidism due to improper storage.
“Blister packaging may eliminate refractory hypothyroidism due to improper storage (123).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [123]
Between 15% and 20% of patients treated with levothyroxine develop refractory hypothyroidism.
“Between 15% and 20% of patients receiving LT4 treatment develop RH. 10”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [10]
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- Authors
- Benvenga, S., Papi, G., & Antonelli, A.
- Affiliations
- University of Messina (IT)
- University of Pisa (IT)
- Corresponding author
- Papi, Giampaolo
- Venue
- Frontiers in Endocrinology
- Publisher
- Frontiers Media SA
- Published
- 2017-07-10
- Volume
- 8
- Pages
- 155-155
- ISSN
- 1664-2392 (ISSN-L)
- PMC
- PMC5502408
- OpenAlex
- W2735882485
- Cited by
- 22
- References
- 22
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 2 · 2018: 3 · 2017: 1
- FWCI
- 0.87
- Type
- journal article
- Language
- it
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Endocrinology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacy and Medical Practices
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- refractory hypothyroidism, levothyroxine, drug storage, serum TSH, hypothyroidism treatment
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