Combination Thyroid Treatment May Be Worth the Risk in Some Cases

Patients who are dissatisfied after treatment with levothyroxine alone stand to benefit the most

With Thanh Duc Hoang DO

Thyroid and pills

Any physician who has treated those with hypothyroidism has undoubtedly encountered patients who have normal TSH levels after treatment with levothyroxine (LT4), but still don’t feel well. While some physicians are willing to try alternative treatments, such as desiccated thyroid extract (DTE) or combination therapy with liothyronine (LT3) and levothyroxine, there has been precious little good research on who might benefit.

A consensus statement on combination treatment released in February 2021 found agreement that further study is needed, and that the investigations should ensure that patients who are dissatisfied with their current treatment – regardless of whether their lab tests are in a normal range or not – are included. It also suggests using patient reported outcomes as a primary outcome, and that patient preference be a secondary outcome.

An estimated 3.7% of the US population has some form of hypothyroidism, whether autoimmune or idiopathic, according to the National Health and Nutrition Examination Survey. The condition results in both cognitive and metabolic symptoms for those afflicted, including depression, weight gain, mental fog, and memory problems. DTE, the original therapy devised for hypothyroid patients, was exclusively used until the 1970s when LT4 was created. Some patients felt the change was detrimental to their quality of life and asked to return to DTE treatment, and studies were designed to determine if adding LT3 to LT4 treatment would alleviate symptoms. However, there was little consistency in the findings.

Another study on whether DTE presented a proven improvement to patients dissatisfied with care found similar improvement between DTE and LT4, although the former also led to a modest weight loss of about 4 pounds. Half the participants also preferred it.

Now, a new study, presented first at the ENDO 2021 virtual conference in April, has compared all three treatments – DTE, LT3/LT4 combination treatment, and LT4 alone – and found little difference in outcomes among the three in general, but that the patients who felt the worst were more likely to feel an improvement on combination therapy using LT3 or DTE.

The study, which is being readied for publication (an abstract can be found here), enrolled 90 patients, 75 of whom completed the study. All were adults aged 65 or younger who had primary hypothyroidism and had been on stable doses of LT4 for at least 6 months, with a daily dose of 75-250 mcg. Outcomes included performance on standardized memory, depression, thyroid symptom, and general health questionnaires or tests. Thyroid function, weight and lipid profiles, and treatment preferences were also gathered from the participants.

In all groups, TSH levels were considered normal, while T3 and T4 levels were impacted in treatment that included LT3 or DTE, with T3 levels 30-50% higher and T4 30% lower. Patients on DTE had slightly higher heart rates, but other data points were similar in all arms. Whether thyroid disease was autoimmune based or not did not impact the outcomes.

What was different was how those who were the worst performers on most of the questionnaires and tests did while taking combination therapy or DTE, showing “substantial improvement” after they switched. There were no statistically significant differences for the memory tests, or biochemical and metabolic data points. The worst performing patients also preferred the alternative treatments.

While most studies on thyroid disorder treatments exclude patients with symptoms such as untreated depression, the authors note that this one didn’t shy away from them and scrutinized participants based on their reported residual symptoms and their satisfaction with LT4 monotherapy. “The patients identified through these methods consistently preferred and performed better while on therapy containing T3, either LT4+LT3 or DTE,” the study notes.

While the mechanisms for why this treatment works better than monotherapy in some patients remain to be discovered, the authors believe this work can be built upon.

In the past, combination treatment with either DTE or LT3 and LT4 combination treatment was considered potentially dangerous to patients’ cardiovascular health, says author Thanh Duc Hoang DO, program director for endocrine fellowship at Walter Reed National Military Medical Center in Bethesda, MD. However, those worries changed as production improved, and none of the patients in this study who were on DTE or combination treatment experienced any such safety issues.

The study was small, says Hoang, but doing a large prospective study can be difficult – it is expensive and time consuming, and funding can be challenging. “But I think this study is a good one and promising for those patients who have a lot of symptoms while taking just levothyroxine. They respond well to either of the alternative treatments.”

Physicians “see these patients all the time,” he says. When those doctors try combination therapy, “they see a big impact on their quality of life and they suffer a lot less.” In Hoang’s earlier study published in 2013, he and his co-authors found it was “reasonable” to offer combination treatment to patients who report not feeling well even though their lab results are normal, says Hoang. But it doesn’t always happen.

According to Hoang it largely depends on the training and experience of the physician. “Some don’t know how to manage these medications, and with DTE in particular, it can be harder to do correctly.”

DTE can make T3 levels lower, and some providers will just see the TSH level as low. “The TSH should be normal and not suppressed,” he says.

As to whether to use DTE or LT3 and LT4 therapy, “it has a lot to do with personal choice of the patient and physician experience working with the drugs,” Hoang notes. “There isn’t really a difference in outcomes. But in my experience if you try liothyronine and a patient doesn’t respond, try DTE. They may feel the difference is like night and day.”

While he knows what can work, Hoang says he still can’t say why some patients feel such a difference, nor do they know the mechanism by which this improvement occurs. How soon those questions will be answered depends a lot on what studies happen in the near future. For his part, Hoang is delving deeper into those who have the highest scores in thyroid symptom questionnaires. “When we look at the general public, we don’t see a lot of differences in the group, but only those who are very symptomatic respond well to combination treatment. We want to discover more about why this group is different.”

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