Association of Low TSH Levels in Hypothyroidism Therapy with Mortality Risk

Introduction

Since the introduction of sensitive tests to determine serum TSH, doctors have recommended that patients with hypothyroidism adjust their levothyroxine dosage to achieve TSH levels within the target therapeutic range. However, a smaller percentage of patients (10–15%) are dissatisfied with levothyroxine monotherapy and continue to experience disease symptoms despite treatment. Some indirect evidence also suggests that normal serum TSH levels may not reflect tissue euthyroidism in patients treated with levothyroxine.

Patients with hypothyroidism thus often require an increased dose of levothyroxine, a combination with liothyronine, or thyroid extract (often purchased online), adjusting their medication based on symptoms, although there is insufficient evidence to suggest that combination therapy is more effective than levothyroxine monotherapy.

Current guidelines recommend not exceeding the upper reference limit of TSH, supported by robust evidence and generally accepted by both doctors and patients. However, adherence to the lower TSH limit in levothyroxine therapy has been controversial until recently.

Study Results

In the past two years, two large-scale population studies have been published evaluating health outcomes in patients with hypothyroidism treated with levothyroxine in relation to serum TSH levels.

Lillevang-Johansen et al. conducted a study with 2,908 Danish patients with hypothyroidism treated with levothyroxine. The median follow-up period was 7.2 years, focusing on mortality compared to euthyroid individuals. The study observed a 5% increase in mortality risk for every 6 months of elevated TSH levels in both treated and untreated patients (for treated: hazard ratio [HR] 1.05; 95% confidence interval [CI] 1.02–1.07; p < 0.0001; for untreated: HR 1.05; 95% CI 1.02–1.07; p = 0.0009). In patients with suppressed or low TSH levels due to excessive supplementation, an 18% increase in mortality risk was observed for every 6 months of reduced TSH levels (HR 1.18; 95% CI 1.15–1.21; p < 0.0001). The findings remained consistent across disease severity and age stratifications.

Thaykaran et al. published a study analyzing data from 162,369 patients with hypothyroidism in the UK. Patients with TSH levels within the normal range showed no long-term negative health impacts. However, increased mortality was observed in individuals with the lowest and highest serum TSH levels compared to those with TSH within the therapeutic range. For patients with TSH < 0.1 mIU/l, HR was 1.18 (95% CI 1.08–1.28; p < 0.001), for TSH 4–10 mIU/l, HR was 1.29 (95% CI 1.22–1.36; p < 0.001), and for TSH > 10 mIU/l, HR reached 2.21 (95% CI 2.07–2.36; p < 0.001). Thus, while increased TSH levels were particularly detrimental, low TSH was also associated with higher mortality risk.

Conclusion

The results of recently published studies suggest that reducing TSH levels below the lower reference limit is also associated with increased mortality. Implementing practices to maintain serum TSH within the target therapeutic range may help reduce mortality risk. It is estimated that this affects 28.3 million patients in the United States and Europe.

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Sources:
1. Perros P., Nirantharakumar K., Hegedüs L. Recent evidence sets therapeutic targets for levothyroxine-treated patients with primary hypothyroidism based on risk of death. Eur J Endocrinol 2021; 184 (2): C1–C3, doi: 10.1530/EJE-20-1229.
2. Lillevang-Johansen M., Abrahamsen B., Jørgensen H. L. et al. Over- and under-treatment of hypothyroidism is associated with excess mortality: a register-based cohort study. Thyroid 2018; 28 (5): 566–574, doi: 10.1089/thy.2017.0517.
3. Thayakaran R., Adderley N. J., Sainsbury C. et al. Thyroid replacement therapy, thyroid stimulating hormone concentrations, and long term health outcomes in patients with hypothyroidism: longitudinal study. BMJ 2019; 366: l4892, doi: 10.1136/bmj.l4892.