Levothyroxine was one of the first drugs I dispensed as a pharmacist where a patient became visibly upset with me after receiving (what she thought) was a generic version of the drug. The store I was working in had recently changed their labelling to show the generic name, instead of the brand name, on each vial. The drug being dispensed didn’t change – just the label. One patient, who had been taking Synthroid (a brand of levothyroxine) for years, was livid with me for suddenly giving her “levothyroxine”. I tried to explain that the drug was the same one that she’d been receiving, that levothyroxine was the generic name for Synthroid, and that I hadn’t actually switched anything. She wouldn’t accept my explanation, stating that her symptoms had worsened since “you switched the drug”. It was an early lesson in how perceptions can shape expectations and even symptoms, in this case, a form of nocebo effects.
The thyroid doesn’t get much attention despite thyroid medications being among the most dispensed drugs in the world. When people start thyroid medication it can become a lifetime therapy. Yet there are persistent concerns that thyroid disorders may be overdiagnosed and overtreated, and that millions may be treated with thyroid medication unnecessarily. Now there’s new evidence to answer an important question about when thyroid medication might be necessary.
Hypothyroidism is the consequence of the thyroid gland failing to produce enough thyroid hormone (My old post gives more background, but I’ll repeat some here). The body produces two thyroid hormones: thyroxine (T4) and liothyronine (T3). Primary hypothyroidism is the result of insufficient production of T4 by the thyroid gland (Secondary hypothyroidism is a consequence of pituitary or hypothylamic disorder). The overwhelming majority of cases of hypothyroidism are primary, and the major cause of primary hypothyroidism is autoimmune thyroid disease (Hashimoto thyroiditis). Iodine deficiency can cause primary hypothyroidism too, but it’s rare in developed countries.
Hypothyroidism may have zero symptoms, but in severe forms can cause coma, organ failure, and death. Patients with untreated but mild primary hypothyroidism sometimes describe weight gain, cold intolerance, dry skin/hair, constipation and hair loss. While the assessment and treatment of hypothyroidism is based around patient-relevant symptoms, the diagnosis of hypothyroidism must be based on lab tests, owing to the non-specific nature of the symptoms. Three laboratory measurements evaluate thyroid function and are used to diagnose hypothyroidism:
- Thyroid stimulating hormone (TSH), secreted by the pituitary, is the primary screening measure in most situations. The normal range is usually reported to be 0.3-5.5 mIU/L, and a diagnosis of hypothyroidism is likely when the TSH is elevated above 10. The less functional the thyroid, the higher the TSH (Values will vary for what is a “normal” TSH depending on the lab).
- Free T4 (FT4) is evaluated when the TSH is abnormal. The usual range is 9-19 pmol/L and will be reduced in hypothroidism.
- Free T3 (FT3) has a usual range of 2.6-5.7 pmol/L. It may be reduced in hypothyroidism, but its value is not useful for diagnosis.
Subclinical hypothyroidism is generally defined as a “normal” T4 and a slightly elevated TSH: That is, some laboratory signs of a thyroid dysfunction, but not sufficient enough to warrant a diagnosis of hypothyroidism. Between 8-18% of adults over the age of 65 are reported to have these laboratory findings. There may be no symptoms, or they can be vague and nonspecific: fatigue, dry skin, constipation and depression. However, there’s an association with coronary heart disease, making the overall significance unclear and raising the persistent question of whether or not it should be treated with medication at all. A 2007 Cochrane Review suggested that treating subclinical hypothyroidism doesn’t seem to result in meaningful differences in symptoms or quality of life, nor does it appear to decrease cardiovascular morbidity. The USPSTF is also skeptical. It notes in a 2015 review:
A large magnitude of overdiagnosis and overtreatment is a likely consequence of screening for thyroid dysfunction, particularly because the disorder is defined by silent biochemical parameters rather than a set of reliable and consistent clinical symptoms. The high variability of TSH secretion levels and the frequency of reversion to normal thyroid function without treatment underscore the importance of not relying on a single abnormal laboratory value as a basis for diagnosis or the decision to start therapy. Currently, it is not possible to differentiate persons who will have advancing thyroid dysfunction of clinical importance from those whose TSH levels will remain biochemically stable or even normalize. Treating the latter group (at a minimum) will not lead to benefit, and these persons may experience harms associated with antithyroid medications, ablation therapy, and long-term thyroid hormone therapy.
There’s some data cited by the USPSTF to suggest that the threshold at which physicians initiate thyroid replacement therapy in subclinical hypothyroidism may be dropping, and consequently more people are being treated. Given the high number of prescriptions, it’s possible that millions of people with no symptoms of hypothyroidism are receiving thyroid replacement therapy. So an important question that’s been asked for some time is if treating subclinical hypothyroidism offers any meaningful benefits to patients. Now we have a trial that gives some important information to answer that question.
Does treating subclinical hypothyroidism help?
This new study from Stott and colleagues, entitled “Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism” was well designed to answer an important clinical question: Does treating subclinical hypothyroidism offer patients any meaningful benefits? This trial was funded by the European Union, and sponsored by several non-profit entities in Scotland, Ireland, the Netherlands, and Switzerland. Supplies of levothyroxine (T4) and the matching placebo were donated by Merck KGaA. The study was randomized, double-blind, and placebo controlled, recruiting 737 adults over the age of 65, who had what would be deemed persistent (3 months to 3 years) subclinical hypothyroidism (they defined it as a thyrotropin level of 4.6 to 19.99 mIU/L, and normal free thyroxine). Patients were excluded if they had taken any thryoid medications, medications that can affect thyroid function, and several other medical conditions. Participants were randomized 1:1 to treatment or placebo. The active treatment arm started with a low dose of levothyroxine, with gradual dose adjustment (by computer algorithm) to bring thyroxine to the normal range (0.40 to 4.59 mIU/L). (There was a mock dose adjustment in the placebo group.)
There were two primary outcomes: thyroid-related quality of life scores, and tiredness scores, measured using standardized tests (from 0-100 with a significant difference being 9). Secondary outcomes included general quality-of-life tests and several other measures, including grip strength. While they had initially planned for cardiovascular events to be a primary outcome, that was changed mid-trial owing to difficulties recruiting patients (which meant the trial would have been underpowered.)
The average age of participants was 74.4 and about half were women. After one year, the average thyrotropin level had decreased to 5.48 mIU/L in the placebo group and 3.63 mIU/L in the treatment group, with a median daily dose of 50 μg of levothyroxine. In short, the levothyroxine did exactly what was expected, which was to bring the thyrotropin down to the normal range. Despite this, the investigators found no difference in the mean change of thyroid-related quality of life scores or tiredness scores between the two groups. There were also no meaningful differences in any secondary outcomes either. In short, treating this “subclinical hypothyroidism” had no effect on any relevant patient-reported or objective measure.
What this means
I love clinical trials that answer a specific and relevant therapeutic question, with the potential for widespread benefit. Overtreatment is a significant issue in medicine, and it’s essential that any medication be initiated with an objective and relevant purpose in mind. This trial showed clearly that treating older adults with subclinical hypothyroidism has no meaningful or apparent benefits to patients. Consequently, it will provide good evidence to inform physician and patient discussions and decisions in evaluating whether or not thyroid medication may be necessary at all.