Why Do Some Patients Not Feel Well on Levothyroxine Therapy?
Introduction
Levothyroxine (LT4) is the standard treatment for hypothyroidism and usually restores normal thyroid hormone levels and alleviates symptoms. However, a subset of patients on LT4 continue to feel unwell despite “normal” thyroid blood tests. Studies estimate that 15–20% of LT4-treated patients have a lower quality of life compared to healthy controls, and roughly one in four patients may report persistent hypothyroid-like symptoms even with a normal TSH (thyroid stimulating hormone) level. This article explores why some patients have persistent symptoms, outlines differential diagnoses and additional testing to consider, and reviews alternative treatment options (like adding liothyronine T3 or using desiccated thyroid extract).
Reasons for Persistent Symptoms and work up
Several factors may contribute to patients feeling unwell on LT4 monotherapy:
Suboptimal LT4 Dosage or Absorption Issues: Some patients require higher doses of LT4 due to poor gastrointestinal absorption caused by conditions like celiac disease, atrophic gastritis, or Helicobacter pylori infection. Medications like calcium, iron, and proton pump inhibitors can also reduce LT4 absorption.
Check for celiac disease antibodies if you suspect gluten sensitivity as the reason for malabsorption.
If you are suspecting atrophic gastritis, you can start the work up with a complete blood count and ferritin. You could also order Parietal Cell Antibodies (PCA)
Advise to take calcium, iron and soy products to be separated from levothyroxine ingestion by at least 4 hours.
Levothyroxine absorption test can also be done to rule out issues with absorption.
Concurrent Autoimmune Diseases (e.g., Addison’s disease, celiac disease, vitamin B12 deficiency)
Patients with Hashimoto’s thyroiditis have a higher risk of developing other autoimmune disorders, which can contribute to fatigue and systemic symptoms. Screening for adrenal insufficiency, celiac disease, and pernicious anemia (B12 deficiency) is recommended in patients with ongoing symptoms.
Check morning (8 am) cortisol and ACTH to rule out adrenal insufficiency.
Check B12 level
Other medical conditions like diabetes or hypertension that are not under control.
Uncontrolled diabetes can lead to fatigue, weight changes, and neuropathy, while poorly managed hypertension can cause headaches, dizziness, and cardiovascular symptoms. Optimizing management of these conditions is essential for improving overall health and symptom resolution.
Anemia and Nutrient Deficiencies: Iron deficiency anemia, and folate deficiency can contribute to fatigue, weakness, and cognitive dysfunction. These deficiencies are more common in patients with autoimmune thyroid disease and should be screened for and corrected when necessary.
Check CBC and ferritin
If folate deficiency is suspected, order Red Blood Cell (RBC) Folate Levels. Elevated plasma homocysteine can be an indirect marker of folate deficiency, but not specific.
Sleep Disorders (e.g., sleep apnea, insomnia)
Obstructive sleep apnea (OSA) is prevalent in individuals with hypothyroidism and can contribute to persistent fatigue. Insomnia and poor sleep hygiene can also impact energy levels and cognitive function.
Sleep studies (home or in hospital) and proper sleep hygiene counseling may improve symptoms.
For insomnia, consider sleep medications.
Mental Health Conditions (Depression, Anxiety Disorders)
Depression and anxiety frequently coexist with hypothyroidism and can contribute to persistent symptoms such as fatigue, low motivation, and brain fog. Psychological evaluation and appropriate treatment, including therapy or medications, can significantly improve well-being.
Fibromyalgia or Chronic Fatigue Syndrome (CFS)
These conditions share many symptoms with hypothyroidism, such as muscle pain, unrefreshing sleep, and chronic fatigue. A thorough evaluation to differentiate these syndromes from residual hypothyroid symptoms is necessary to ensure appropriate treatment.
Medication Side Effects: Certain medications, such as beta-blockers,and antidepressants, can mimic or exacerbate symptoms of hypothyroidism, including fatigue and cognitive dysfunction. Reviewing a patient’s medication list and adjusting or substituting medications when appropriate can help alleviate symptoms.
Pituitary or Hypothalamic Disorders (Central Hypothyroidism): In central hypothyroidism, TSH is often low or inappropriately normal, making free T4 and T3 the primary indicators of thyroid status. Patients with pituitary disease often require individualized LT4 dosing, targeting free T4 in the upper normal range to ensure adequate hormone availability.
Overtreatment or increased sensitivity to Thyroid Hormone: Some patients may experience symptoms of hyperthyroidism, such as anxiety, palpitations, and insomnia, even when TSH is within the normal range / on the lower side. This may be due to individual sensitivity to thyroid hormone levels or excessive LT4 dosing. Reducing the dose while monitoring symptoms can help restore balance.
Time-Course Factors: Recovery from hypothyroidism is not immediate, and some symptoms may take months to resolve after achieving biochemical euthyroidism. Patients with high health-related anxiety may misinterpret normal fluctuations in energy and mood as continued hypothyroidism. Education and reassurance can be valuable in these cases.
Incomplete T4-to-T3 Conversion: Levothyroxine gets converted to T3, the active hormone, in tissues. Some patients may not convert T4 to T3 efficiently, leaving tissues relatively T3-deficient despite normal blood T4 and TSH. For example, LT4-treated patients as a group have a ~15–20% lower T3:T4 ratio and about 15% fail to maintain normal T3 levels in serum. A common genetic variation in the Type 2 deiodinase enzyme (DIO2 Thr92Ala polymorphism) has been linked to impaired psychological well-being on LT4 alone and reduced T4-to-T3 conversion. These findings suggest that standard LT4 therapy might not fully restore tissue T3 levels or euthyroidism in every individual. Indeed, one clinical trial found that adding T3 improved mood and neuropsychological function in LT4-treated patients, supporting the idea that T4 alone may be inadequate for a subset of patients. In such patients treatment that contains T3 might be helpful.
Alternative Treatment Options for Persistent Symptoms
If a patient’s LT4 dose is optimized and other conditions have been ruled out or treated, yet they still feel poorly, clinicians and patients may consider alternative thyroid hormone therapies. These include:
Combination Levothyroxine + Liothyronine Therapy (T4/T3 Combination)
Desiccated Thyroid Extract (DTE)
In patients with absorption issues - liquid levothyroxine or gel capsules can be considered.
Conclusion
While levothyroxine monotherapy effectively treats most hypothyroid patients, a considerable minority experience ongoing symptoms or intolerance. A careful differential diagnosis and targeted testing are essential to uncover contributing factors. If persistent symptoms remain after optimization of standard therapy and management of comorbidities, individualized treatment approaches can be explored. Patient-centered care, regular follow-ups, and therapy adjustments based on subjective and objective measures can help optimize well-being.
References
Peterson SJ, Cappola AR, Castro MR, et al. An Online Survey of Hypothyroid Patients Demonstrates Prominent Dissatisfaction. Thyroid. 2018;28(6):707-721. doi:10.1089/thy.2017.0681
Hidalgo J, Vallejo BA, Soto Jacome C, et al. Real Practice Assessment of Persistent Symptoms After Initiation of Levothyroxine. Endocr Pract. 2024;30(2):95-100. doi:10.1016/j.eprac.2023.10.132
Vargas-Uricoechea H, Wartofsky L. LT4/LT3 Combination Therapy vs. Monotherapy with LT4 for Persistent Symptoms of Hypothyroidism: A Systematic Review. Int J Mol Sci. 2024;25(17):9218. Published 2024 Aug 25. doi:10.3390/ijms25179218
Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999;340(6):424-429. doi:10.1056/NEJM199902113400603