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2009-02-24 Stella L Volpe, PhD, RD Thyroid Function Zinc And Iron

How Do Zinc and Iron Nutrition Affect Thyroid Function?

An Interview with Dr. Stella Volpe, Ph.D.

KIRK HAMILTON: My name is Kirk Hamilton, PA-C and welcome to Prescription 2000 Expert Interviews.  I am very pleased today to have Dr. Stella Lucia Volpe as our guest, speaking on the roll of zinc and thyroid function.  This interview is based on Dr. Volpe and her colleagues paper entitled “Effect Of A Zinc Supplementation On Thyroid Hormone Function: A Case Study Of Two College Females,” Ann Nutr Metab, 2007;51(2):188-194. 45371

KIRK HAMILTON: Hello Dr. Volpe.  Thank you so much for coming on the phone today.

DR. VOLPE: Thank you for having me Kirk.

KIRK HAMILTON: As I announced previously, you wrote an article and you and your colleague called the Effect of zinc supplementation on thyroid hormone function: A case of two college females, an analysis of nutrition and metabolism in 2007.  And so, it has taken us a year or two, but we finally got there to talk about it.  But before I get into that topic, tell us a little bit about your background, your educational background and how you got where you are and what your status is at that moment and your interests.

DR. VOLPE: Sure, my BS is actually in exercise science from the University of Pittsburg and my Masters is in exercise physiology from Virginia Tech and my PhD. is in nutrition from Virginia Tech and then I did a post doc. Back at UC Berkeley and then headed to University of Massachusetts where I was a professor for about 10 years and then took a position as a faculty member as a professor here at University of Pennsylvania and my research interests lie in really assessing how either minerals or exercise and diet or the environment all impact diabetes and/or obesity.   And in the paper to which you are referring the idea was to evaluate how zinc could affect thyroid hormone function which in turn could affect body weight.

KIRK HAMILTON: This brings me to the question of then,  how does zinc, the biochemistry of zinc, effect thyroid function or actually the production of thyroid hormone?

DR. VOLPE: Sure.  Zinc is all the minerals that we require is a crucial enzyme for more than 300 metabolic reactions in the body and one of those reactions is the conversion of thyroxine, T4, to T3.  Those are thyroid hormones in our body and what zinc does, and I will get back to the thyroid hormones in a second, is convert thyroxine T4 to triiodothyronine which is T3, and that is the more active thyroid and it does that by implementing its effects on an enzyme called 15 prime deiodinase and when we think about the fact of thyroid hormone impacting almost every metabolic process in our body that is a pretty crucial of zinc.

KIRK HAMILTON: Well that brings up a point then.  So, doctors many times will just do a TSH and maybe a free T4, but they do not measure T3.  So can you tell the audience what are the metabolic consequences or what advantages or how powerful this T3 is metabolically active part of this thyroid hormone production.

DR. VOLPE: Sure.  T3 is actually the most active one.  And one of the reasons that T3 is not always directly effective because what a lot of the time happens, in the defense of the measurements of these is if TSH, thyroid stimulating hormone is not active, that in and of itself can cause someone to say, have a hypothyroid condition.  And having hypo or hyperthyroidism can lead to many things.  Problems in the body, metabolic processes, not just weight problems.  It can lead to many other processes that can go sort of wrong in the body.  So in their defense that is the most common way that we can see hypo- or hyperthyroidism in testing it.  But, from a nutritional standpoint, what is not often assessed are things like zinc and by the way iron is also involved with these deiodinase enzyme as well.  I am probably getting a little ahead of myself, but the reason we really wanted to evaluate this was to say, you know what, in particular in athlete’s were the population we evaluated was that a lot of times female college athletes, in particular, may or may not be overweight, but they try to regular their body weight and often times when young women regulate their body weight one of the first things that they will take away from their diets are meats, and red meat, aside from oysters, red meat is a really high food source of zinc and that is sort of where this whole issue of zinc thyroid hormone function, body weight regulation all occurred in our thought process.

KIRK HAMILTON: So these are under converters of T4 to T3.  Is that what you are hinting at?

DR. VOLPE: Well what we call them are metalloenzymes.  That zinc and, I will say iron, but because we are focusing on zinc, I will just say zinc.  Zinc is required basically for  the deiodinase enzyme to convert T4 to T3.  The thought process in my head is well, and by the way this came about from others who have studied this, in my thought process was well often times there might be trouble with people trying to lose weight, they might not necessarily have a problem with their thyroid hormone per se, it could be a problem with their dietary intake of zinc and that is what we were out to assess with this particular study.

KIRK HAMILTON: But the sequelae of that is a low-normal T3.

DR. VOLPE: Right, the sequelae would be the low-normal T3, correct.

KIRK HAMILTON: And that makes it more difficult to lose weight.  Because I measure both T3 and free T4 on everybody.  So you know you frequently see a normal T4 and a very low normal T3.  So the point I was trying to get at is why does most of medicine and I see that from colleagues that, you know, we see patients from, they very rarely and many endocrinologists never do T3, hardly at all.  And, you have people complaining of traditional thyroid symptoms of difficulty losing weight, constipation, hyperlipidemia, fatigue, etc. and you do not see it measured.  I mean, I, you are one step ahead of the ball game even thinking about the conversion and zinc and nutrition.  I mean there are people not even thinking about who cares about T3, that is the point I am trying to make.  Give me reasons to share with my colleagues that it is important to have a mid-range normal or upper normal T3.

DR. VOLPE: Sure, my apologies for not quite getting that question.  You know because T3 is the most active form of the hormone, that is what will affect the body, that is what will effect thyroid metabolism, will effect whether someone is hyperlipidemic or not, the whole fatigue issue.  So like you, I am one to, in my research, I try to evaluate more than just the pre-product, I guess is what I would say.  I like to look at what is a prehormone, not that thyroxine is a prehormone, but the predecessor, as well as the end product.  And, if I can digress just a second, this was actually a  discussion in my metabolism class last night because we were discussing vitamin D and my students asked, often times 25-hydroxy vitamin D is evaluated, but not the 125-dihydroxy vitamin D3 that is the most active form and we sort of got in the same discussion because as a researcher I think we need to look at both.   And, as clinicians, I think it would behoove clinicians to look at both because that can give you a better picture of what is going on with that person.

KIRK HAMILTON: So, can I have a normal free T4 and then I have a low-normal T3, and most physicians will not touch that if the TSH is in the normal range, and the normal range for TSH keeps getting smaller and smaller.  So, are we talking about someone struggling with losing weight, fatigue, I know some psychiatrists, traditionally who use T3 strictly for depression.  So, what are the clinical things that the physician might get extra oomph out of if he paid more attention to T3, that he would not T4 or is it all the thyroid hormone functions.

DR. VOLPE: I would say it would be everything that you earlier stated.

KIRK HAMILTON: Why do we even care about normalizing T3 when T4 is normal and then the TSH is normal to the average physician, why do we care?

DR. VOLPE: I guess when we think about the fact that T3 is not that I guess, but when you realize the fact the T3, of all of those is the most powerful form of the hormone and that is the hormone that implements the greatest effects on the body.  That by ignoring T3 it almost basically ignoring the end product.  Not that T4 and TSH do not count, but T3, if I can make an analogy is like the worker bee and by ignoring that, even if its predecessors are available, if the conversion is not happening then what we expect to happen normally in the body may not be happening.  In particular, if a patient is saying that they are feeling the effects of what we would consider hypothyroidism, and that is being ignored, then over time that will get worse.

KIRK HAMILTON: Then your concern from your physiologic and nutritional background is that, and you are
seeing it from, and you talked about athletes, their food intake might not be adequate and they
are low in zinc and iron is also important for the conversion of T4 to T3.  Is not selenium
important for that conversion as well?

DR. VOLPE: Selenium not as much as iron and not as much as iodine.  Those would be much more minerals that are involved in thyroid hormone metabolism than selenium would be.  Somewhat involved, but not quite iron and zinc for that conversion are really required just for that 15 prime deiodinase.

KIRK HAMILTON: Okay, well let’s talk about what happened in your study.  Why did you happen to run into two
female college students and ended up talking about the study.

DR. VOLPE: First of all, I want to say that I want to make sure that my former graduate student Christy Maxwell, the first author on this, I just want to make sure I mention her name.  So this was part of her Masters Thesis and just to be clear, our goal was that we were going to assess a larger number than just a case study.  So clearly as a researcher, we like to have large sample sizes so that we can more generalize our findings to the population.  Unfortunately, when my graduate student was trying to recruit participants for this study, and this happened over a couple of years period of time.  We actually found it somewhat difficult because we were trying to find zinc deficient women and our initial part of the study, the way we were trying to find zinc deficient women were finding people who were athletes, and who were vegetarians because both of those things can lead to zinc deficiency.  And when I say that, I don’t mean that exercise leads to zinc deficiency.  I want to clarify the fact that by not eating zinc sources of food, i.e. meat products, that can lead to zinc deficiency.  But the stressor of exercise might lead to transient zinc deficiency and combine with the vegetarian diet perhaps the person could become frankly zinc deficient.  The goal was let’s recruit as many people as we could.  The bad part was we only found two women who were zinc deficient.  Hence the reason this was published as a case study.

KIRK HAMILTON: Tell me how you define zinc deficiency.

DR. VOLPE: Zinc deficiency was define as less than 0.7 mcg per mL and that was ...

KIRK HAMILTON: In the serum?

DR. VOLPE: In the serum and I will clarify something in a second.  Actually we evaluated in the plasma and we used an atomic absorption spectrophotometer which is a common laboratory instrument to measure plasma zinc.  Now let me clarify, however, that there is definitely argument among scientists that plasma zinc status alone may not be the best indicator for zinc status, but at this moment what we use in the field is plasma zinc status and so we based it on 0.7 mcg per mL and they had to be below that and of course when we measured things, we measured them after a 12-hour fast; we measured things in triplicate so that we knew that we were getting the proper, you know, average of the samples and has low co-efficient of variations within our sample evaluation and then we wanted to supplement that.  So, again the idea was over a four month time, let’s start with zinc deficient women and then lets supplement them and what we did was we gave them 26.4 mg of elemental zinc.

KIRK HAMILTON: Can I interrupt just for a second.  When you found that they were zinc deficient, it was out of how many women you found? And were they athletes?

DR. VOLPE: Yes, my goodness, I will tell you that over a couple of years, and this was through several different graduate students, but Christie was one of them and took her a couple of years.  We evaluated well over 50 potential participants, where we took their blood and they were woman athletes and then I will tell you what we did because we were not finding zinc deficiency, we expanded it to either just athletes who were not necessarily vegetarians or vegetarians who were not necessarily athletes.  So we expanded because we were not finding any zinc deficient women and then what happened was of course, is we only came down to these two who met our criteria, which were pretty strict, but who met our criteria of zinc deficiency.

KIRK HAMILTON: Did these people have low T3 levels or T4 levels and elevated TSH or did you do that concurrently?

DR. VOLPE: Excellent question and no not concurrently and I will explain why that was not done currently.  The idea was we wanted to see: Does zinc deficiency lead to this decrease in T3, if we indeed have zinc deficient and in this case women, will that lead to decreased thyroid hormone function?  And the other reason we did not do all the thyroid hormone analysis at the beginning was actually sort of on a practical sense.  This was not a largely funded, highly funded study, so when we order or radio amino assay kits, we are ordering them all at the end of study.  We properly freeze them and then we can do them all within the same batch and with the same lot number because they are done in my lab.  So that is on a practical reason that is why they were not done initially.

KIRK HAMILTON: So you screened these 50 some odd patients, or these college students, and you found two that were zinc deficient.  You had to work hard at it.   Then did you assess their thyroid function?  Because how would you know if you gave zinc if it improved or not?  I am kind of confused.

DR. VOLPE: Oh sorry, we did evaluate thyroid hormone function.

KIRK HAMILTON: Once you found they were deficient, the two deficient ones.

DR. VOLPE: Correct.  I guess in your initial question was.  Did we do that in the beginning as far as we did not say you have to be zinc deficient and thyroid hormone deficient.  The criteria for entering into the study was you had to be zinc deficient, i.e. plasma zinc level less than 0.7 mcg per mL.  Once we had that, we collected enough blood at baseline and two and four months.  It was a four month study, that when we collected blood at those time points, we also evaluated thyroid hormone function.  However, all the hormones were not evaluated until one batch at the end.  Radio immunoassay kits are expensive and we only had two participants and so in that respect we did that at the end, but did a baseline test.

KIRK HAMILTON: Were these two zinc deficient females low-normal or low in serum free T3 and T4 at the time you diagnosed them with low zinc.

DR. VOLPE: You are saying baseline, were they also below normal levels.

KIRK HAMILTON: So, you have your baseline free T3 and free T4 and you start a supplement with 26.4 mg of zinc from zinc gluconate and may I ask how they took that?  Anytime during the day?  With food?  One pill a day? Or was that split in divided doses?

DR. VOLPE: They actually took one in the morning and one in the evening because the doses came from the lab at 13.2 mg and that is why it is such a defined dose because we actually had it analyzed , so we just told them to take one in the morning and one in the evening.

KIRK HAMILTON: With food? Or it does not matter?

DR. VOLPE: It does not really matter.

KIRK HAMILTON: Okay.  And tell us what you found?

DR. VOLPE: So what we found was again just with two subjects, but when we look at the total T3 and that is measured in nanograms/deciliter, both subjects started off around the hundred range; one was 113 about, and one was 98.9.  One subject increased over time, we measured remember baseline, two months and four months.  The difference over time was that one subject increased by about 7 units and the other by about 88 units.  When you look at total T4, actually subject one declined by about 1 unit and the other increased by 2 and with free T3 and free T4 we see the same pattern again.  But subject one decreased ever so slightly like 0.1 and 0.2 and subject 2 increased ever so slightly at 0.9 and 0.12.  Finally, with TSH we see the same pattern; so that subject one decreased slightly and then subject two increased by about one point.  So this is what is hard, as a research when we only have two participants.  We cannot do any statics on this.  But, from what it appears, if we were just to look at total T3, that......

KIRK HAMILTON: Total or free T3?

DR. VOLPE: Total T3, if we look at total T3, because that is where sort of our data looks the best.  So, if I can play my data a bit here, which I should not really do, but I am going to, in the sense that if we look at total T3 both participants after zinc supplementation had an increase.  I cannot tell you if it is significant or not; again, because no statistics can be done on two subjects.  If you look at free T3, there is a mixed bag.

KIRK HAMILTON: Theoretically, that is the free hormone and that is what does the action, correct?

DR. VOLPE: Correct.

KIRK HAMILTON: So, where there any symptoms assessed before and after the supplementation to see if the bottom line as a clinician is that people feel better.  So, was there anything assessed in that regard or was it strictly by the numbers of zinc levels and T3, T4 changes.

DR. VOLPE: We did not have any validated questionnaire to say, you know, are you feeling better, etc.  Because, honestly, even at baseline it is not to say that either one of these participants thought they felt any differently.  But what I can tell you are a couple of other things that we measured.  Well, we measured a lot of things actually.  So, we measured obviously body weight, etc.; but we measured plasma zinc as we should because we wanted to ensure that did it increase, and indeed both of them increased and they both came from at 0.63 and 0.69 to above 7.7 for both of them, micrograms per mL.  We also measured resting metabolic rate because and percent body fat in lean mass.  And the reasoning behind that is, because zinc effects the conversion of T4 to T3 and T3 impacts metabolic rate; not only did we want to measure a biochemical measure, but we wanted to measure sort of this clinical variable resting metabolic rate and if RMR (resting metabolic rate) measured in kilocalories per day decreases, then percent body fat may, as a result increase, because of the decreased metabolic rate and what we found was that over time, that both the women increased their resting metabolic rate.  Now one increased by about 200 kcals per day; the other increased by almost 1,000 kcals per day.  So another scientist can look at these data and argue to say that well maybe in your one participant that was just coefficient of variation error, whereas the other one perhaps was a difference due to the zinc.

KIRK HAMILTON: Was there any changes in weight or lean body mass?

DR. VOLPE: We saw an ever so slight decrease in percent body fat and a slight increase in lean mass.  So if were indeed expecting a change we would have hopefully had a bigger change.  But, it still went in the direction we would hope for as far as if indeed the zinc had an impact and I really want to be careful how I relay the message about this study because it is a case study that I cannot definitely say one way or the other, as I said earlier, because our sample size here are two participants.

KIRK HAMILTON: Would looking at a bigger clinical view.  I mean I see patients every day and we would not be looking at high end athletes as much as we would be looking at the average, let’s say, 25-45 year-old female who is struggling with weight and it is very easy to measure free T3, free T4 and TSH; we do it all the time.  It is very easy to measure serum zinc levels.  If you found people who are low in zinc or low normal in zinc, if you were going to supplement, let’s say their T3 levels are low normal, which I see a lot of, a lot of low-normal T3 levels, how long would you say you have to wait to be fair to see some maybe improvement with zinc supplementation.?

DR. VOLPE: That is an excellent question.  We actually would expect to see some changes within several months and let me tell you why.  A lot of research that has been done on zinc, have shown that even over maybe a two month period you might expect some changes.  One of the classic studies, and this was done a while ago, was by Dr. Janet King and colleagues, who happened to be my postdoctoral advisor at UC Berkeley. Basically one of the many things Dr. Janet King did was to evaluate if they first depleted zinc in people and then they gave them zinc and they found that zinc actually could have trends toward increasing DMR and TSH and T4 concentrations.  Most studies on zinc, either based on Dr. King’s studies or based on other studies, many times supplement studies on zinc can last from two to six months.  So really we would expect the impact, I would not say fairly quickly but I would say in at least the four months that we established was somewhat based on other supplement studies.  Your question is a good and fair question, however, because there are many things that go on in a free living human that we cannot always control and some of them could be either what they are eating, what they are doing, the stressors in their life, if they are actually taking the supplement, adhering to taking the supplement and/or if their absorption of that supplement is different from one person to the other.  So I think it would be fair to say, even though I am talking to you from a research perspective of what we might expect, probably in a variation we see among individuals I think giving a good six to eight months would be a fair estimation to see if it impacted and what.

KIRK HAMILTON: And see as a clinician, we you have a patient in front of you and let’s say.... it is very easy to do the assessment part, because I do it every day. But, to tell someone okay they are fatigued, they are wiped out, and there is a million reasons for that.  But if this is a component just give me a little T3 and T4, that would be the patients desire because they want to feel well, and it would be the clinicians tug because he wants to help them improve more quickly.  I tried to supplement over the years, and probably not patient enough with the zinc and the selenium and iodine and tyrosine actually as well.  And that is the problem from a clinical point of view.  You know people come in and you have a change that subtly over four to six, eight months would be real tough for a patient to be fired up about.

DR. VOLPE: Right.

KIRK HAMILTON: In review, just about your concept here.  Just review one more time, the nutrients that you feel are involved in thyroid function, very simply and then what you would like to see from this work.  Would you be looking more at athletes, would you be looking at the average person in society, aside from the intellectual curiosity of a researcher, how would you like to see this applied?  Maybe start with that question first.  How would you like to see this applied if it is true, you know, that zinc helps in the conversion and you could help people, would you say screen people for zinc deficiency or what would you say?

DR. VOLPE: It is always fun when people ask you those kinds of things about your research because it gets me thinking a little differently.  I honestly do want to somehow impact the world with my research.  You know, I don’t want to just do research for research sake right and I misquoted myself in saying that earlier that by the way selenium is involved in thyroid hormone metabolism as you know.  But, if I were to think about this research, of course I would feel better if we had a larger number of subjects that I could tell you, you know what we really found this and this should happen clinically.  But being as it is, and that this has been published as a case study and also another study that we conducted with iron and thyroid hormone function was another case study because of a difficulty of not finding iron deficient women who were not already supplemented.  I would like to see, and I do firmly believe that it would be prudent for clinicians to evaluate plasma iron and zinc status.  And I know iron is more commonly evaluated clinically because of iron deficiency anemia, but if iron and zinc status could be evaluated it just would help give a better picture of what might be going on with a person.  And although I realize that many people may very well benefit and probably need synthetic thyroid hormone, my gut tells me that there are still a good percentage of people who may be zinc deficient and/or iron deficient who could benefit from supplementation and or probably supplementation and not just dietary changes if they are truly deficient.  And that is where I feel like that can be an inexpensive safe way to help people who might have this, as you even said earlier, this slightly low T3 level and maybe are considered okay.  And maybe those are the people we target first as far as evaluating zinc and iron status.

KIRK HAMILTON: Well, the one thing that I can take as a clinician, I mean it is hard to keep a person, saying I am going to help you in six to eight months.  I am just telling you flat.... that is a hard thing to say to a patient who is miserable.

DR. VOLPE: Oh I hear you.

KIRK HAMILTON: I use both synthetic T3 and T4 and I will actually use Armour Thyroid which is desiccated thyroid and see people improve.  They just do.

DR. VOLPE: Right.

KIRK HAMILTON: And you know you can get criticized for that, and you try to stay in the normal ranges, but you see people improve that would normally be called normal thyroid patients just because they are in this broad range of normal.  But what has opened my eyes as a clinician would be that I will look more at iron...because I have kind of forgotten about that in the sense for thyroid function.  I test serum zinc a lot and I see it low-normal in elderly subjects quite frequently.

DR. VOLPE: Not surprising.

KIRK HAMILTON: And I think more of that as for immune enhancement in the elderly and things like that.  But I see it low normal a lot and I do it almost routinely in my elderly patients.  I don’t normally do it in the midrange female which might be something that I would consider.  And iron, I do quite frequently, but I will think about it a little differently when I do that.  I am going to wrap this up.  But I just want to thank you very much and hopefully we will do this again soon and any time you do some research on thyroid and nutrients, because it is a very hot topic, especially in what I would say if alternative or preventive medicine circles. Thyroid is looked at as something that is ignored and though many given thyroid hormones, T3 and T4 and measure the free levels of free T3 and free T4, the nutrient part I would like to be able to share more of.  So any time you do research on that, send me a paper and we will review it.  Okay.

DR. VOLPE: It has been my absolute pleasure.  Thank you so much.

KIRK HAMILTON: I would like to thank Dr. Volpe for her time and expertise and sharing with us the concept that zinc and iron nutrition are important in conversion of T4 to T3 and that may be important in improving thyroid function.  One key is that if you are going to supplement with zinc and iron and assess for it, it is going to take a long time.  So clinically that is a tough call for a patient and a tough call for a clinician to say you might have a subclinical thyroid issue and it may take six months to a year to normalize out.

I want to thank you for listening to Prescription 2000 Expert Interviews and we will talk to you soon.

 

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