Over- and Under-Treatment of Hypothyroidism Is Associated with Excess Mortality: A Register-Based Cohort Study
Abstract
OBJECTIVE: This study investigated the association between hypothyroidism and mortality in both treated and untreated hypothyroid patients, and the consequences of over- and under-treatment with respect to mortality. PATIENTS AND METHODS: This was a register-based cohort study of 235,168 individuals who had at least one serum thyrotropin (TSH) during 1995-2011 (median follow-up 7.2 years). Hypothyroidism was defined as at least two measurements of TSH >4.0 mIU/L within a half year spaced by at least 14 days, or one measurement of TSH >4.0 mIU/L and two filled prescriptions of levothyroxine the following year. All-cause mortality rates were calculated using multivariable Cox regression analysis adjusted for age, sex, and comorbidities using the Charlson Comorbidity Index. RESULTS: Mortality was increased in untreated hypothyroid individuals (n = 673; hazard ratio [HR] = 1.46 [confidence interval (CI) 1.26-1.69]; p < 0.001) compared to euthyroid controls. Results remained significant even when subdividing according to mild (TSH >4.0 mIU/L and ≤10 mIU/L; p < 0.001) and marked hypothyroidism (TSH >10 mIU/L; p = 0.002). Mortality was increased in both treated and untreated hypothyroid individuals for each six months a patient had increased TSH (HR = 1.05 [CI 1.02-1.07], p < 0.0001, and HR = 1.05 [CI 1.02-1.07], p = 0.0009, respectively). In patients who received levothyroxine, the HR for mortality increased by a factor 1.18 ([CI 1.15-1.21]; p < 0.0001) for each six months a patient exhibited decreased TSH. This finding was essentially unchanged after stratification by disease severity (mild or marked hypothyroidism) and age (older and younger than 65 years). CONCLUSIONS: Mortality was increased in untreated but not in treated hypothyroid individuals, independently of age and severity of hypothyroidism. Duration of decreased TSH in treated individuals had a greater impact on mortality than did duration of elevated TSH. These results stress the need for close monitoring of treatment in individuals receiving thyroid hormone replacement therapy.
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The detrimental effects of both over- and under-replacement have been reported.
“The detrimental effects of both over- and under-replacement have been reported (94, 95).”
From ETA guidelines for the use of levothyroxine sodium preparations in monotherapy to optimize the treatment of hypothyroidism (2025) · cites this paper as [94]
Long-term over-treatment is associated with well-established risks of cardiac arrhythmia, stroke and osteoporosis, while under-treatment may be associated with impaired well-being, dyslipidaemia and cardiovascular disease.
“Long -term over -treatment is associated with well -established risks of cardiac arrhythmia, stroke and osteoporosis, while under -treatment may be associated with impaired well -being, dyslipidaemia and cardiovascular disease. 31,68”
From Use of liothyronine (T3) in hypothyroidism: Joint British Thyroid Association/Society for endocrinology consensus statement (2023) · cites this paper as [68]
Excessive levothyroxine treatment in patients of high age is associated with increased mortality.
“Excessive LT4 treatment in patients of high age is associated with an increased mortality.”
From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [44]
Several studies showed insufficiently treated overt and/or subclinical hypothyroidism as well as excessively replaced hypothyroid patients are associated with increased early mortality risk in older patients.
“However, several studies showed insufficiently treated overt and/or subclinical hypothyroidism as well as excessively replaced hypothyroid patients associated with increased early mortality risk in older patients [41–44].”
From Risks of suboptimal and excessive thyroid hormone replacement across ages (2023) · cites this paper as [44]
Supratherapeutic levothyroxine doses can cause cardiac and bone toxicity and are associated with increased mortality risk.
“as the use of supratherapeutic doses of LT4, can result in cardiac and bone toxicity, as well as being associated with an increased risk of mortality.[12][13][14]”
From Refractory hypothyroidism: unraveling the complexities of diagnosis and management (2023) · cites this paper as [14]
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Medically not yet explained symptoms in hypothyroidism
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Self-citation
- Authors
- Lillevang-Johansen, M., Abrahamsen, B., Jørgensen, H. L., Brix, T. H., & Hegedüs, L.
- Affiliations
- Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark.
- University of Southern Denmark (DK)
- University of Copenhagen (DK)
- Odense University Hospital (DK)
- Venue
- Thyroid
- Publisher
- SAGE Publications
- Published
- 2018-05
- Volume
- 28
- Issue
- 5
- Pages
- 566-574
- ISSN
- 1050-7256 (ISSN-L)
- 1557-9077
- OpenAlex
- W2797362459
- Cited by
- 150
- References
- 41
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 22 · 2023: 20 · 2022: 24 · 2021: 25 · 2020: 8 · 2019: 16 · 2018: 4
- FWCI
- 10.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Thyroid (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Funders
- Odense Universitetshospital
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- hypothyroidism, mortality, levothyroxine, overtreatment, undertreatment, thyroid-stimulating hormone, thyroid hormone replacement, euthyroidism, disease severity, age
- MeSH terms
- Medical Overuse, Adult, Aged, Denmark, Female, Humans, Hypothyroidism, Male, Middle Aged, Mortality, Registries, Thyrotropin, Thyroxine, Incidence, Hormone Replacement Therapy
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