And I am happy to give you my thoughts on some aspect of thyroid which is very, very clinical and clinically oriented. Now, how many of you treat thyroid, hypothyroid patients in your practice? Almost everybody. How many of you see unhappy hypothyroid treated patients? Almost 50%. How many of you use T3 to help the unhappy thyroid patient? Very few. Okay. Talk is over. Well, so let me see if I can convince you that there is an alternative to what you do. So there are many here that I do not know, but as William Yates, the famous Irish philosopher said, there are no strangers here, just friends that you have not met, yet met. No disclosures. So hypothyroidism, a very common clinical problem, 5% prevalence in the U.S. and probably the same here. Far more common in women. The most common type is, cause is autoimmune thyroid disease, which commonly we refer to as Hashimoto. Gold standard is hypothyroid, treat with thyroxin. Our treatment is established almost for 70, more than 70 years. It is safe, and as noted by many of you, it is what you use. The goals of hypothyroid treatment, four. Number one is to alleviate relief symptoms, normalize TSH, improve quality of life, and avoid overtreatment. These are thyroid hormone preparations that are available. I know you are familiar with them. We will not discuss details, only to say that there is thyroxin, there is triiodothyronine, and there is thyroid extract, the natural preparation. All three of them are available for you to use. You can use one or an alternative. Thyroid hormone therapy tells us that 97% of the thyroid hormone use in the U.S. is levothyroxine, and I think that probably is true also here, as indicated by this small sample here. In 2020, there were 100 million prescriptions of levothyroxine in the U.S. alone. The vast majority of patients were happy, and they were taking their medication, and we have no problems. However, almost 10% of the treated patients described unhappiness, unsatisfaction, and symptoms with continued treatment. So the challenge is why and what to do with this. So in my practice, the unhappy patient profile is typically this, a white, obese woman who is between the ages of 20 and probably 50 years, hypothyroidism has been present for many years, the usual cause is Hashimoto thyroiditis, patient has been on thyroxine, TSH is normal, patient is referred or patient comes to us, self-referred for evaluation, the patient is often frustrated, she is unhappy, she says her local team did not help her, and so she looks at us armed with disinformation from the internet saying, what else can you do and what about T3? They actually ask us for an alternative. What about thyroid extract or T3? So we have to be able to answer those questions. So in 2018, a survey showed that 15% of patients were dissatisfied with their treatment. Satisfaction was highest with desiccated thyroid extract, next with combination T4 and T3, and least satisfaction with thyroxine alone. Causes not identified, but they were said to be multiple. This was in 2018. This is the most recent European multinational survey that confirms that same finding. This was several thousand physicians were surveyed to see what is their practice, 98% used thyroxine alone, they reported that 10% of their patients complained of symptoms despite adequate treatment documented by normal TSH, and when they looked for causes, they recorded psychologic, comorbidities, and unrealistic expectations as the usual causes for dissatisfaction. And then combination therapy was used by almost 40% of those who participated in this survey, which is a high number. Here there was, I think, about 10%. And when they looked at the details of who prescribed combination therapy, women endocrinologists or physician, female, number two, those who had high volume practice saw more patients, and those who were in wealthier countries, I guess in Europe, that would qualify for Northern Europe, Denmark, Scandinavia, et cetera. The conclusion was that the combination T4 and T3 therapy is frequently used by European specialists, and this is now 2024 survey for hypothyroid patients. So my patients tell me the following. They complain of cognitive impairment. This morning, Dr. Fabian mentioned brain fog. That is a common term that my patients use. Low energy and chronic fatigue, poor quality of life, unable to go to school or perform tasks, mood issues, and then difficulty with weight. If you ask patients specifically what they report to you, there are many. These are some of those. It makes me feel like dumb and ineffective, extreme exhaustion, a dream state but you are awake, severe fatigue which feels like I am through a sludge, and brain fog. These are what patients report, and I think you probably have similar findings. Now, so what are possible reasons for this dissatisfaction? Well, it could be said that perhaps they don't have hypothyroidism. How many of you think that this would be true? Only a few. Well, they could be poorly managed. Maybe I'm not giving enough to my patients. Maybe TSH levels are not reliable. Maybe patients are overwhelmed by chronic disease, or maybe there are so many comorbidities that they overwhelm the patient and we cannot separate those from hypothyroidism. There is, this is a report from my colleagues at Mayo, 30% of alleged hypothyroid patients did not have hypothyroidism. And so this is an important issue that we have to pay attention to. Not only that, but you can look here and see that subclinical hypothyroidism, mild, very mild hypothyroidism accounts for the majority of patients who were in this report were on thyroxotherapy. So if they're unhappy, maybe they just didn't have the right disease and we were not treating the right person. Comorbidities are also very important in overlapping with hypothyroid symptoms, diabetes, obesity, hypertension, sleep disorder, D deficiency, and of course autoimmune disorders. So autoimmune disease itself, and we'll come to this in just a moment. Now in looking for dissatisfaction, we often think of how to resolve this. So we say, okay, let's try to fine tune the treatment. I will try to increase thyroxine dose and I will keep the TSH as close to 0.5 as I can to improve symptoms. Number two is that thyroxine monotherapy does not normalize T3 levels, therefore I like to add T3 to the combination. That's the rationale for treatment. Maybe T4 to T3 conversion is somehow disturbed and that happens by deiodinase. Maybe autoimmune disease, maybe Hashimoto, patient has Hashimoto and has autoimmune disease, that in itself is a factor in complaints. How about very high TPO titers? Could that be a cause? And there may be other causes. I will review some of these very briefly. So remember that fine tuning of thyroxine dose is not evidence-based. There is no evidence that says that if you try to increase the dose and move TSH from 3 to 2 or from 5 to 4 or 1 is evidence-based. There is no science behind that. This is probably the best mostly quoted study from Australia. Carefully designed, a small number of patients were given different doses of thyroxine as you see here, TSH levels, 2.8 to, that should be 1.0 and then 0.3. So they tried to titrate TSH levels to lower levels by increasing thyroxine dose but they could not find satisfaction or improved symptoms in surveying these patients. So it looks like fine tuning is not an effective answer. This is a recent, more recent study of patients who were unhappy, were given increasing doses of thyroxine. And the authors I have highlighted, the findings found that thyroxine treated subjects preferred the higher doses, when they found out the higher doses, but there was no actual, by objective assessment, better quality and results. And so why thyroxine monotherapy may not be enough and why do our patients complain? Well, there could be type 2 deiodinase deficiency, which conversion of T4 to T3. There could be polymorphism, a congenital abnormality that may have deficiency in this conversion. It is also true that as you increase thyroxine doses, the conversion decreases. So in fact, when we are giving more and more thyroxine, we are reducing serum T3 levels, which is something that we like to achieve. And some patients on thyroxine treatment do not feel normal because T3 levels in the brain. So whatever we measure in serum may not necessarily apply to what is present in brain. This is a normal person. 85 microgram of thyroxine is secreted from thyroid, six and a half microgram of T3, but there is a significant component of T3 from conversion of T4 to T3. When there is no normal thyroid, then in hypothyroid person, we add thyroxine, and the thyroxine is the source of T3 that is generated in the system. And the iodinase two is the key here to convert thyroxine to T3. So the logic for combination therapy is the following. Some hypothyroid patients remain symptomatic despite normal TSH. Some of these patients have subnormal low serum T3 levels. T3 deficiency is likely accounting for continued persistent symptoms. Let's add T3 to T4 so that we overcome this deficiency. Is it true that patients with thyroxine therapy only have low T3? This is a recent report showing that almost 40% of patients who were taking thyroxine have low T3 levels. So it is true that if you administer only thyroxine, T3 levels are lower than normal, at least in this study, in this report, by almost 40%. So if that is true, then let's try to give T3 and T4 and see what happens. And here are, as far as I could tell until recently, 18 randomized clinical trials of combination T4 plus T3. 883 patients, they compared with T4 monotherapy. The combination therapy seemed to have no significant advantage in improving psychological health. However, some patients at the end of the study, when they were told you had combination therapy, preferred combination therapy. So objective evidence, none. Subjective evidence, positive. So the conclusions from these studies, I think it is important for me to summarize and emphasize the results here. There were 18 studies so far, combination therapy. These results were, those who don't like these results say they were negative. Let's try some more. They were not negative. Oh, sorry, they were not inconclusive. They were actually negative. We don't need any more data on this topic. There were 18 studies consistently showing that T4 plus T3 is not better than thyroxine alone. So I think the case is closed. We just have to look for something else. Now it is also true that in these patients, and in your practice, when you give T3, when you add T3 to T4, patients like it. So 42%, 52% of patients who were given T3 and T4 preferred combination over monotherapy. So that is true, and this is a subjective finding. So there is also one problem with polymorphism, congenital abnormality of the iodinase preventing conversion of thyroxine to T3. That happens, it is true, it is very rare, and it only happens in occasional families. It is not a systemic widespread problem. But it is true that those patients who do have this problem, if you give T3 and T4 to normal population, not everybody is improved. When there is a single SNP, or single nuclear polymorphism, 63%, or if there are two polymorphism deiodinase problems, almost everybody benefits from treatment. So in this very small category, there is documented improvement. But this is unusual. There is also to the randomized clinical trials, these people have Hashimoto, thyroidectomy, et cetera. The question was, and the objection is, that these patients were not uniform and they were given thyroxine and T3 once a day. So in this new study, all these patients were thyroidectomized and T3 was given in two doses per day, and still, objectively, there was no improvement in symptoms. There is additional information on desiccated thyroid extract comparing with monothyroxine therapy. Studies show that there is no improvement. So desiccated thyroid, not better than thyroxine alone. So, there is, in many of our hypothyroid patients, an underlying mood or depressive disorder. And there are studies that suggest that perhaps there is a higher element of impression from these creating continued unhappiness and symptoms. Occasionally, we get a question from public regarding what to do with unhappy hypothyroid patients. This is one recent communication that a patient is asking for latrexone, which is a medication used for addiction, anti-addiction, to see if that would destroy my thyroid so that I feel better, and we answer that, no, that is not the case. And then finally, what about high antibody titers? This is a report from a recent report in the Annals of Internal Medicine from Scandinavia, showing from Norway, showing that patients that had very high TPO titers were very much symptomatic. So, they randomized treatment to thyroxine therapy and thyroidectomy. And in those that had thyroidectomy, fatigue score significantly improved, and percentage of those who improved was much higher. All parameters improved in those who were thyroidectomized. And they removed the thyroid. Therefore, the TPO antibody dramatically declined, and with the decline, as compared with normal that had symptoms, there was no symptoms. So, the conclusion from this report is that very high TPO titers, thyroidectomy, removal of the thyroid, is key and helpful. So, why combination therapy remains controversial in 2024, and why am I giving you this talk? It's because many of the blinded studies failed to confirm that combination therapy is better, that there is no reported difference in clinical outcomes between T3 and T4 versus monotherapy, thyroxine, that fine-tuning of thyroxine dose is not helpful, and administration of T3 may cause undesirable drug peaks. So, the guidelines, I have them here. I see that Dr. Alzahrani is waiting for me to finish, so I will not review these, but the trend has been to approve combination therapy through the past decade. Guidelines are saying, well, previously, the guidelines suggested no need, but now they are saying, if your patient is unhappy, try give a trial, this trial, a chance. And so, here is the practice trend use of combination thyroxine and T3 is now generally recommended for some hypothyroid patients who continue to have symptoms despite normal TSH. And here is a report that shows that between 2013 and 2018, in just five years, there was a significant increase in T3 use. In Denmark, both endocrinologists and general practice have used combination therapy in increasing numbers. And in the U.S., combination therapy, as well as desiccated thyroid use, has increased in the past decade. So, the trend clearly is there. The question is, is T3 administration safe? The question is, is T3 administration safe? And despite the fact that if you give a high dose of T3, there's a peak, generally speaking, long-term T3 use is considered safe. And so, you and I will see a patient in our clinic on come Monday. What do we do with this patient? First of all, I have learned to listen and to discuss the problem carefully with my patients. Secondly, we evaluate comorbidities. We try to address those, treat those, and see what does that do to the well-being of the patient. We explain risks and benefits of combination therapy. At the end, if the patient wants to, I will offer combination therapy. My practice is that if a patient comes to see me on combination therapy, I do not try to dissuade or discourage patient from continued use of it. So, when do you consider adding T3? Hypothyroid patients who are not happy with their treatment, when serum T3 levels are low in reference, lower than reference range, documented that they have deficiencies. Serum T3 is 60 or 70. Hypothyroidism is associated with depression and the reason for this is that in psych literature, the T3 is often used for patients who have depression. So, if they already have depression, you could make a case for adding T3 to help both depression and hypothyroidism. When do we avoid it? In the elderly, in pregnancy, and in patients with cardiac disease. This is just something that you can use in your practice in case you want to do T3. There are many ways to do it. You reduce thyroxine dose and you add increments of T3 to achieve or to maintain a normal TSH level. And so, take home messages from this brief talk. Normalizing thyroid hormone homeostasis and resolving all symptoms with daily tablets of just levothyroxine may not be realistic. So, some of our patients will continue to have problems even though we have tried our best and we keep them clinically and biochemically euthyroid. While most patients are happy with thyroxine alone, there is an occasional patient in our practice who doesn't like thyroxine alone. And if that is the case, after discussion, then you can offer them T3, T4 combination. But before doing that, make sure that you evaluate and address and treat underlying comorbidities. Treatment with T4 and T3 seems to be effective in some cases and it is safe. When I say effective, I am, like you, disregarding randomized clinical trials and I tell my patients, you know, there is no science, but let's try this and that's where I can leave you. Thank you very much.

hypothyroidism

levothyroxine

combination therapy

Hashimoto's

T4 and T3

patient dissatisfaction