RUSH UNIVERSITY MEDICAL CENTER
By Maggie Van Dyke
Jan. 11, 2016
Looking back in time can reveal missed connections and unanswered questions that are worthy of re-examination today. That’s what endocrinologist Elizabeth A. McAninch, MD, learned when she started digging through old medical textbooks to detail the history of hypothyroidism — that is, an underactive thyroid.
McAninch assumed that she’d find evidence supporting the current treatment for hypothyroidism — which has been the standard of care for about four decades — as being superior to other therapies. Instead, she discovered a major gap in scientific research, as described in an article published in the Jan. 5 issue of the Annals of Internal Medicine. An assistant professor in the Division of Endocrinology and Metabolism at Rush, McAninch co-authored the article with Antonio C. Bianco, MD, PhD, president of Rush University Medical Group and vice dean of clinical affairs at Rush Medical College.
Hypothyroidism is a condition caused when the thyroid gland in the front of the neck doesn’t produce sufficient quantities of thyroid hormones, which are important in many processes in the body, including growth, development, metabolism and cognition. About 10 million people in the U.S. have this condition, according to McAninch, and it is especially common in women. In the very early stages it may not cause symptoms, but over time, untreated hypothyroidism can cause significant health problems, such as cognitive dysfunction, infertility, cardiac disease and slowed metabolism.
“What we all learn in medical school today is that hypothyroidism treatment is straightforward,” McAninch says. “Patients are treated with levothyroxine, a synthetic thyroid hormone, and the majority of patients do really well on this therapy.”
Even after taking levothyroxine, however, about 15 percent of patients still suffer troubling symptoms, including fatigue and forgetfulness. This quandary led McAninch and Bianco to wonder how the medical community came to agree that levothyroxine by itself (i.e., levothyroxine monotherapy) should be the first line treatment.
Before that protocol became commonplace in the 1970s, patients with hypothyroidism typically were given a desiccated (or dried) form of thyroid gland harvested from animals. Because the thyroid gland contains both types of thyroid hormones, triiodothyronine (T3) and thyroxine (T4), patients treated with desiccated thyroid received a combination therapy, in contrast to patients receiving levothyroxine monotherapy, which only contains only T4.
McAninch’s historical research surprised her. “I had assumed that levothyroxine monotherapy had been shown to be superior than other therapies, that it was either more efficacious or safer. I had assumed that appropriate comparative clinical trials had been done with modern techniques and measures,” she says. “But the bottom line is these studies have not been done — and still need to be.”
What led us here?
To identify the major historical turning points in hypothyroidism treatment, McAninch and Bianco decided to go back 120 years. “PubMed (a search engine for online medical research) and the Internet didn’t exist back then, plus a lot of medical science was not published in journals at that time,” McAninch says.
“So we scoured bookstores for old books on thyroid disorders and collected a library of endocrinology textbooks across the decades. Then I went through every single book — easily over 50 books — and wrote down the hypothyroidism medication that was recommended, along with the dose, during each time period.”
After putting all this information into a timeline, McAninch pinpointed when treatment recommendations changed to support levothyroxine monotherapy, and why. She learned that the majority of patients did relatively well on desiccated thyroid, but the capsules themselves were a problem.
“They would crumble or lose their efficacy when stored in humid conditions. So people were upset about the inconsistency of those tablets,” she explains. “Also, overdose was commonplace in the early 20th century. because doctors did not have access to the type of blood tests available today that can measure the amount of thyroid hormones in the blood and ensure safe levels.?
Then, in the early 1970s, scientists discovered that the body converts the T4 hormone to T3. “So scientists and clinicians both suggested, ‘If the human body can produce its own T3, then taking T4 must be enough to replace thyroid hormone.”
As a result, it became more popular to give patients synthetic levothyroxine monotherapy —which, remember, is T4 alone. The pills could be produced consistently without any storage issues, and patients would make their own T3 by taking the T4.
The rest, as they say, is history. Since the majority of patients with hypothyroidism do well on levothyroxine monotherapy, which is also a very safe medication, there has been limited interest in conducting time-consuming and expensive clinical trials comparing treatment options to address the minority of patients with residual symptomatology.
Where do we go now?
However, recent discoveries suggest that the human body may not be as efficient at turning T4 into T3 as previously believed. For one, patients who are treated with levothyroxine monotherapy tend to have relatively low or lower-than-normal T3 levels. This difference may help explain the minority of patients who remain symptomatic.
Animal studies by Bianco, McAninch and other scientists provide further support for this theory. When animals with hypothyroidism were treated with levothyroxine, blood tests suggested they had normal thyroid hormone levels. However, researchers found that their brain and other tissues were still exhibiting markers suggestive of hypothyroidism.
McAninch hopes that her paper in addition, to their other research findings, prompt expanded, clinical trials soon that compare the efficacy and safety of combination T3/T4 therapy to levothyroxine monotherapy. Until that happens, physicians can continue to follow the recommendations of the American and European Thyroid Associations, which now support trials of combination T3/T4 therapy in patients who do not respond adequately to levothyroxine monotherapy.
Given the contemporary emphasis on evidence-based medicine, McAninch also sees tremendous value in researching the historical precedence behind many of today’s well-accepted treatment regimens.
“I think the historical methodology I used for hypothyroidism could be applied to other diseases and illnesses,” she says. “We really need to make sure that the current standard of care we are applying in the clinic and teaching our medical students has been shown to be the safest and most efficacious approach.”
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