Two months after his new book, Rethinking Hypothyroidism, hit the shelves, Antonio Bianco, MD, PhD, talks to Endocrine News about, well, rethinking hypothyroidism. From his research of thyroid metabolism and deiodinases to why researchers and clinicians have often been so mystified by hypothyroidism for centuries, Bianco discusses why treating hypothyroidism is a “solution followed by a mystery.”
This past November, Antonio Bianco, MD, PhD, a physician-scientist at the University of Chicago published his book, Rethinking Hypothyroidism, which offers an accessible overview of the treatment of hypothyroidism, and makes the case that the current approach is failing many patients. For Bianco, two of his patients shed light on the fact that patients with hypothyroidism can remain symptomatic despite treatment.
His book goes to exhaustive lengths to help readers understand why some recommendations in the clinical guidelines are flawed; it details the history of the clinical characterization and treatment of hypothyroidism, starting with Napoleon Bonaparte and leading all the way up to the present; and provides scientific evidence supporting the claims and complaints of millions of patients over the past 50 years.
Endocrine News sat down with Bianco to discuss his career, balancing his dedication to science with his dedication to his family, and why the medical community should always be willing to question even long-held beliefs in order to help patients.
Endocrine News: Tell us a little about yourself. What attracted you to medicine? From there, what led you to endocrinology and the thyroid?
Antonio Bianco: I always wanted to be a scientist. I was curious about how things work and my older brother being a physician influenced me into biology and chemistry (while in medical school I pursued a second degree in biology, studying at night). During the first years of medical school, I joined the Department of Physiology as a TA and soon was helping graduate students with their theses. My mentor worked in the thyroid field, hence my focus on the thyroid gland. We were studying the influence of caloric intake and dietary composition on the thyroid gland. Later I joined J. Enrique Silva’s lab at the Brigham and Women’s Hospital in Boston. He was the advisor of my PhD thesis on the thermogenic effects of thyroid hormones.
EN: Tell us about your involvement with the Endocrine Society. What got you involved with the Society? Are there any special moments that you can reflect on?
AB: I attended ENDO in 1988 and have attended most meetings since then. Enrique was my sponsor. ENDO is the place where you meet everybody and see what is going on in the endocrine world. I have attended many other endocrine meetings around the world, but nothing compares with ENDO. I have served on a number of committees and recently had the pleasure of serving on the program committee. My special ENDO moment was in 2011 (93rd meeting) when I gave a plenary lecture about tissue-specific regulation of thyroid hormone action.
EN: What have been some of the most rewarding moments of your career? Most challenging?
AB: Every time a scientist makes a discovery, graduates a student or a fellow, or receives an award is a rewarding moment. For me, having served as President of the American Thyroid Association in 2016-2017 has been my greatest honor, probably the most rewarding moment. The biggest challenge has always been balancing dedication to an academic career and to my family. I have triplets, they are 21 years old now, but I had to be there for them while running a lab, mentoring fellows, and renewing grants.
“The story of hypothyroidism treatment presents a solution, followed by a mystery. Why did so many of those treated for hypothyroidism ultimately fare so poorly? How was a century-long medical triumph transformed into a tarnished victory, fraught with conflict and exhaustion? Why did doctors dismiss the millions of patients insisting their treatments were failing; and why did patients find themselves suddenly doubting decades of reliable, tested science?” – Antonio Bianco, MD, PhD, professor of medicine; member, Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, Illinois
EN: Your work in deiodinases and thyroid metabolism sounds like quite a eureka moment. (Or several eureka moments building off one another.) Is that fair to say? Can you speak more to this work?
AB: We are all used to the idea that hormone levels fluctuate in the blood and, as a result, their actions in organs and tissues can be easily detected. For example, during fasting your insulin levels in the blood are low, thus not much glucose transport is happening in tissues that depend on insulin. After a meal, insulin levels increase 2-3-fold and glucose enters many tissues. Well, the thyroid hormone levels in the blood are stable, they fluctuate only minimally. Thus, it was difficult to understand how a hormone that is stable in the blood can initiate actions in organs and tissues.
My initial interest in this area formed while I was a graduate student at a time when the enzymes that metabolize thyroid hormones, i.e., the deiodinases, were being characterized. The work done during my PhD, and later by my fellows, showed that by metabolizing thyroid hormone (transforming T4 to T3) deiodinases can increase T3 levels in organs and tissues (and initiate thyroid hormone action), without affecting the levels of thyroid hormones in the blood. So, if one only looks at the hormone levels in the blood, they will miss all the action that is happening inside the organs and tissues.
EN: Now to your book, Rethinking Hypothyroidism. Can you give us an overview of the text and what to expect from the book?
AB: The book is about treatment of hypothyroidism. It is for patients and for physicians. I felt that to make a meaningful contribution to the field, I had to engage both at the same time. Thus, writing for both groups was quite a challenge.
Hypothyroidism is a disease that affects about 20 million people living in the U.S. So, it is a big deal. The book starts by describing the crisis we have today, i.e., between 10% and 20% of the patients remain symptomatic despite being treated adequately as prescribed in the clinical guidelines. Physicians have been slow in recognizing these residual symptoms as a failure of the treatment with levothyroxine (LT4). We knew about these symptoms but learned since the 1970s that they were not thyroid-related. Patients feel dismissed. Many are angry. In the book I explain how this came about and the role played by the pharmaceutical companies, influencing physicians into believing that treatment with LT4 is flawless, superior to other forms of replacement therapy, which created a dogma and lack of curiosity or effort for investigating residual symptoms. This was reflected in the clinical guidelines prepared throughout the years.
Next, I talk about how the metabolism of thyroid hormones is critical for the effectiveness of the treatment for hypothyroidism. Without the deiodinases, which transform T4 to T3, LT4 could not be used in the treatment of hypothyroidism. I also talk about history, including things I saw first-hand and things I learned from several interviews in preparation for this book. Then I move to the treatment of hypothyroidism, starting in the early 1800s when goiter and cretinism were common, and the subsequent description of hypothyroidism and development of the first treatment forms.
Then I tell the story of the discovery that a unique feature in the way the type 2 deiodinase (D2) is metabolized (ubiquitinated and degraded in the proteasomes) helps explain why treatment with LT4 fails some of the patients with hypothyroidism. I also tell about my participation in clinical trials, which shed light on how we can help these patients that remain symptomatic on LT4. Lastly, I provide treatment alternatives and a perspective of where the treatment of hypothyroidism could be moving to in the near future.
EN: Can you speak a bit more about how big pharma has shaped hypothyroidism treatment?
AB: From 1890 until 1970 the standard of care for the treatment of hypothyroidism was with thyroid gland and then with desiccated thyroid extract (DTE). DTE is obtained from a pig thyroid and contains the two main thyroid hormones, i.e., T4 and T3. DTE was cheap and effective, but it had issues with potency. In other words, standardization of the strength of the different lots and brands was sub-optimal and the amounts of T4 and T3 for each lot or brand could vary substantially. With the discovery that the body converts T4 to T3, physicians at the time reasoned that treatment of hypothyroidism could be done with T4 (LT4) only, and the body would produce sufficient amounts of T3 (the biologically active thyroid hormone), thus resolving all symptoms.
Well, the pharmaceutical industry pushed this narrative without solid evidence obtained in clinical trials. We, physicians, believed it without asking for the evidence. Clinical trials to compare DTE and LT4 were never done, never asked by the FDA, never recommended by clinical guidelines. We adopted LT4 as the standard of care for hypothyroidism without testing its effectiveness or safety in randomized clinical trials. Well, as it turns out, treatment with LT4 that normalizes serum TSH levels does not restore thyroid hormone economy in all patients with hypothyroidism (there is always a relative insufficiency of T3 and, in about 15% of the patients, T3 levels are below the normal reference range). Most patients do well on LT4 despite these limitations, but 10-20% don’t. In the book I use reports from the New York Times and Wall Street Journal among other things to explain how this happened and blame myself as well for not realizing it in time.
“ENDO is the place where you meet everybody and see what is going on in the endocrine world. I have attended many other endocrine meetings around the world, but nothing compares with ENDO.” – Antonio Bianco, MD, PhD, professor of medicine; member, Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, Illinois
EN: Tell us a little about how the book came to be, the research and interviews, and what you might have learned in your research that you might not have known before.
AB: I had most of the book in my mind for the last five years. When I connected the dots (much later then I thought I should have) and realized what was happening, I thought to myself I need to write a book and tell more people what I learned. With the pandemic, things in the lab slowed down and I had more time, which I used to write the book. I used Zoom to interview many people. I travelled to the Mayo Clinic to research their historical museum. Because since 2010 (this was when I saw two key patients with hypothyroidism) I had refocused my research to understand the shortcomings of therapy with LT4, I, of course, included a lot of research from my lab into the book.
EN: You talk about the knowledge gap that doctors have of not being aware that patients with hypothyroidism remain symptomatic. Can you speak a little more to that?
AB: We have known about these residual symptoms for decades. Somehow, they were overlooked and did not make it into the clinical guidelines. We should have been warned about them, but we were not. Instead, we were told to treat patients with LT4 to a dose that normalizes the levels of TSH in the blood, and at that point patients should be symptom-free. Any residual symptoms are not thyroid-related. This narrative has been told for 50 years now, in books, medical school, clinical training, in conferences. Some of us were skeptical about it since the 1970s. After seminal studies done in the U.K. and the Netherlands, we learned for a fact in the early 2000s that the narrative was not entirely true. But we kept going. Do you know how many times I affirmed to my patients that their complaints of weight gain and poor memory associated with hypothyroidism were not thyroid related? And I explained that their serum TSH was normal, which meant that thyroid hormone economy had been normalized? Countless. Everybody did the same thing. And yet, even at that time there were studies showing that the basal metabolic rate was not fully restored with the normalization of serum TSH. We should have investigated this further. Today, when I speak those patients, I feel embarrassed.
EN: Your book has a section for patients that will help them in discussions with their doctors. Can you give an example? On that note, what advice do you have for doctors on the other side of those discussions?
AB: The book should empower both patients and physicians to have a good conversation about residual symptoms of hypothyroidism. First, it is clear that these symptoms exist, and they are thyroid-related. (of course there are also symptoms that are not thyroid-related and I discuss in the book how to screen for those symptoms). Second, many patients with residual symptoms do benefit from therapy containing a combination of LT4 and liothyronine (T3). This is supported by clinical trials. Physicians have been told not to use LT3 in the treatment of hypothyroidism because it is ineffective, and because it could lead to cardiac arrythmias and osteoporosis. Today there is good evidence that LT3 is effective for those patients that remain symptomatic on LT4 and, when properly used at the indicated doses, it has been shown to be safe. I was surprised to learn that today there are almost 2 million patients in the USA using either LT3 or DTE for the treatment of hypothyroidism.
“We are all used to the idea that hormone levels fluctuate in the blood and, as a result, their actions in organs and tissues can be easily detected. … Well, the thyroid hormone levels in the blood are stable, they fluctuate only minimally. Thus, it was difficult to understand how a hormone that is stable in the blood can initiate actions in organs and tissues.” – Antonio Bianco, MD, PhD, professor of medicine; member, Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, Illinois
EN: What are some of the new and future technologies for the treatment of hypothyroidism you’re most excited about?
AB: In the book I talk about (i) new T3-like drugs that can make its absorption smoother, avoiding peaks in the circulation, (ii) new T3-like drugs that act selectively in certain thyroid hormone receptors, allowing physicians to enhance thyroid hormone action in organs that remain relatively hypothyroid (liver for example), (iii) stem-cell technology to develop thyroid organoids, which have been transplanted into mice and successfully treated hypothyroidism; this could be a reality for patients sooner than we think.
EN: Finally, what do you hope readers take away from your book? Why should they pick it up?
AB: I like to say that the story of hypothyroidism treatment presents a solution, followed by a mystery. Why did so many of those treated for hypothyroidism ultimately fare so poorly? How was a century-long medical triumph transformed into a tarnished victory, fraught with conflict and exhaustion? Why did doctors dismiss the millions of patients insisting their treatments were failing; and why did patients find themselves suddenly doubting decades of reliable, tested science? How did the case of hypothyroidism backtrack from “closed” to “open”? Most important, what can these patients who continue to suffer do? This book tells that story.
Bagley is the senior editor of Endocrine News. He writes the “Trends” column each month, so anyone with brand new, published research should contact him at: [email protected].