From the Guidelines
For a 57-year-old male with rising TSH despite increasing levothyroxine doses and good compliance, the most critical step is to investigate potential causes of levothyroxine resistance, starting with evaluating medication administration and checking for interfering medications or substances, as suggested by the guidelines for diagnosis and management of subclinical thyroid disease 1. When approaching this patient, consider the following potential causes:
- Medication administration errors, such as not taking levothyroxine on an empty stomach, which can affect absorption
- Interfering medications or substances, including calcium supplements, iron, antacids, proton pump inhibitors, sucralfate, cholestyramine, and certain foods like soy or high-fiber products
- Malabsorption conditions, such as celiac disease, H. pylori infection, atrophic gastritis, or other gastrointestinal disorders
- Liver and kidney function, as these organs play a role in levothyroxine metabolism
- Autoimmune thyroiditis, which can be evaluated by measuring anti-thyroid antibodies
- Bioavailability issues, which may be addressed by trying a different levothyroxine formulation or brand
- Laboratory errors, which should be ruled out by repeating thyroid function tests In rare cases, consider thyroid hormone resistance syndrome, particularly if the patient lacks typical hypothyroid symptoms despite high TSH, as noted in the context of subclinical thyroid disease management 1. Measuring free T4 and free T3 levels alongside TSH would provide valuable information about thyroid hormone status and conversion efficiency, helping to guide further management decisions, in line with the principles outlined for screening for thyroid dysfunction 1.
From the FDA Drug Label
Persistent clinical and laboratory evidence of hypothyroidism despite an apparent adequate replacement dose of levothyroxine sodium may be evidence of inadequate absorption, poor compliance, drug interactions, or a combination of these factors Assess compliance, dose of medication administered, and method of administration prior to increasing the dose of levothyroxine sodium The patient has good compliance, so you should be looking for/testing:
- Inadequate absorption: potential causes include gastrointestinal disorders or other conditions that may affect levothyroxine absorption
- Drug interactions: potential interactions with other medications that may affect levothyroxine levels or activity
- Other potential causes of increasing TSH despite increasing dose, such as changes in the patient's clinical status or underlying condition 2
From the Research
Potential Causes of Increasing TSH
- Poor patient compliance with levothyroxine tablets is a common cause of elevated TSH levels, however, the patient in question has good compliance 3
- Other possible causes of increasing TSH despite increasing dose of levothyroxine include:
- Inadequate serum free T3 concentrations, as some patients on levothyroxine replacement therapy may have higher serum free T4 and lower serum free T3 concentrations compared to euthyroid individuals 4
- Polymorphism in type 2 deiodinase, which may require combined treatment with levothyroxine and liothyronine 5
Diagnostic Considerations
- Repeat thyroid function tests should be performed to confirm the diagnosis of subclinical hypothyroidism, as 62% of elevated TSH levels may revert to normal spontaneously 5
- TSH goals are age-dependent, with a 97.5 percentile (upper limit of normal) of 3.6 mIU/L for patients under age 40, and 7.5 mIU/L for patients over age 80 5
- Serum free T4 and free T3 concentrations should be measured to assess the adequacy of levothyroxine replacement therapy 4
Treatment Options
- Combined treatment with levothyroxine and liothyronine may be considered for patients who are dissatisfied with levothyroxine monotherapy, especially those with a polymorphism in type 2 deiodinase 5
- The benefits and risks of combined T3/T4 therapy should be carefully evaluated, as it may result in wide fluctuations of thyroid hormone levels 6