After learning that 5% of the population has subclinical hypothyroidism, I’m actually more inclined to believe that normal doses of dietary lithium may be causing the obesity epidemic than I was before reading this post. However, my credence is still well below 50%, so I also still agree with your post’s title.
I’m a bit confused about this update. A lot of chronic diseases are very common. And as I showed, hypothyroidism has not been increasing over time. It might be decreasing. And, again, the geographical pattern of hypothyroidism does not match the geographical pattern of obesity.
And as I showed, hypothyroidism has not been increasing over time. It might be decreasing.
I’m specifically considering subclinical hypothyroidism. From the paper you link:
A significant limitation to this report is that the incidence rates of thyroid disorders were based on diagnoses recorded on standardized medical records. Because of this, the findings reflect the rates of thyroid functional abnormalities that were clinically detected and exclude subclinical dysfunction since not all service members are tested for thyroid disorders.
And, again, the geographical pattern of hypothyroidism does not match the geographical pattern of obesity.
If we’re working with the “lithium causes a desire to overeat and be sedentary (via hypothyroidism and possibly other mechanisms) in young people, which leads to lifelong obesity-promoting eating and activity habits” version of the hypothesis, then it may just be that Brazil and China are only now gaining the wealth and food supply to permit this to occur in a large enough swathe of the population. We see obesity growing exponentially in China and India (I couldn’t find a graph for Brazil), while it’s looking like it’s on the concave part of the sigmoid curve in the USA.
I’m inclined to think that if lithium is causing obesity in this manner, that subclinical hypothyroidism is one of its important mechanisms of action. If treating subclinical hypothyroidism in young people did not lead to long-term lower rates of obesity, I would lower my credence in an important dietary lithium-obesity link significantly.
The other paper I linked, which uses nationally representative data from the 2007-2012 NHANES, estimated the prevalence of subclinical hypothyroidism to be 3.5% (lower than the prevalence in the 1988-1994 NHANES, which was 4.3%), and noted that the prevalence of at-risk TSH levels seems to have decreased or remained stable with time. (Although mean TSH levels have increased.)
(I apologize for not having replied earlier — I was curious and wanted to check the raw NHANES data on TSH levels myself before replying to you, so I tried to, but found that parsing one of the datasets was too hard and ended up not doing it.)
[ETA: actually, the 4.3% number is based on a different definition of hypothyroidism. With regards to the definition used in the newer study (TSH > 4.5 mIU/L in the absence of clinical hypothyroidism), it says the following:
Percent reference population with TSH > 4.5 mIU/L for this study was found to be 1.88% which is similar to what was found by Hollowell et al. [Hollowell et al. is the group that analyzed ’88-’94 data]. It would indicate that at risk TSH levels in the reference U.S. population may have decreased a bit or remained at the same level for reference US population.
(I apologize for not having replied earlier — I was curious and wanted to check the raw NHANES data on TSH levels myself before replying to you, so I tried to, but found that parsing one of the datasets was too hard and ended up not doing it.)
No worries, thank you for all the great research you’re doing.
The analysis of ’88-’94 data says:
Hypothyroidism was found in 4.6% of the U.S. population (0.3% clinical and 4.3% subclinical)
The analysis of ’07-’12 data says:
The prevalence rate of clinical hypothyroidism in general U.S. population was 2.4%… The percent population with subclinical hypothyroidism was 3.5% (Table 3).
So we see a 20% decrease in subclinical hypothyroidism (4.3% → 3.5%), but an 800% increase in clinical hypothyroidism (0.3% → 2.4%).
My original argument was based on prevalence in the population, not rate of change across time. If anything, given that (as these papers state), clinical hypothyroidism most definitely is associated with BMI, I think they lend support to the hypothyroidism/obesity explanation. Perhaps what we are seeing is a more rapid move in individual patients from subclinical to clinical hypothyroidism, as a result of the hypothesized lithium contamination. In affected patients, by the time the medical system catches it, it’s usually already clinical, whereas in the (postulated) less lithium-contaminated 80s, there was a longer period of time in the subclinical phase per patient when contact with the medical system could catch and diagnose subclinical hypothyroidism.
I will however make a couple meta notes:
a) I’m not putting as much time into this as you, so I’m worried I’m losing track of the details of the argument.
b) I’m trying to salvage the lithium theory because I don’t think it’s utterly destroyed by this data, not because I think it’s extremely likely.
So I generally just have to apologize if, on reflection, my overall argument here is full of incoherencies and inconsistencies. I’m forming my thoughts as I write these comments, and I expect to change my mind in the future—I’m just not sure in which direction.
So we see a 20% decrease in subclinical hypothyroidism (4.3% → 3.5%), but an 800% increase in clinical hypothyroidism (0.3% → 2.4%).
The abstract of the paper analyzing ’88-’94 data says that they used a different definition of “subclinical hypothyroidism” than the definition that is commonly used today (I had edited my comment to reflect that a few seconds before you replied. I am so sorry for the error!!). Quoting from the paper:
(Subclinical hypothyroidism is used in this paper to mean mild hypothyroidism, the term now preferred by the American Thyroid Association for the laboratory findings described.)
So it seems that the prevalence of hypothyroidism was 4.6% in this survey, not 0.3%. So the prevalence of clinical hypothyroidism has decreased.
With regards to what we nowadays call subclinical hypothyroidism (TSH > 4.5 mIU/L in the absence of clinical hypothyroidism), the paper that analyses ’07-’12 data does say:
Percent reference population with TSH > 4.5 mIU/L for this study was found to be 1.88% which is similar to what was found by Hollowell et al. [Hollowell et al. is the group that analyzed ’88-’94 data]. It would indicate that at risk TSH levels in the reference U.S. population may have decreased a bit or remained at the same level for reference US population.
Note: I’m a little bit sick today, and it’s possible I made a mistake in my stoichiometry or in converting from math to reasoning. If so, I will happily stand corrected if anybody points out my error.
The change in terminology is just verbiage. In fact, it appears they have narrowed the definition of both subclinical and clinical hypothyroidism in the newer paper. In light of how they changed the definitions, we should think that a definition-neutral rate of both subclinical and clinical hypothyroidism has gone up even more than I’d described in my previous comment.
Hypothyroidism is defined in part by lower-than-normal thyroxine (T4). In the earlier paper, T4 levels are defined as “clinical” that would be defined as “normal” or “subclinical” in the later paper. According to the definitions of the later paper, all “subclinical” patients in the earlier paper would have been considered “normal.”
They switched from measuring bound + unbound thyroxine (T4) to free thyroxine (FT4) in the second paper. So the numbers aren’t directly comparable because they’re measuring the molecule in two different states the body. I don’t know whether we can do more than rely on the researchers’ implied claim that the definitions of normal vs. subclinical vs. clinical hypothyroidism remain comparable under the new definition.
Extracts and calculations for legibility:
’88-’94 paper:
… high T4 is a concentration 169.9 nmol/liter and low T4, a concentration 57.9 nmol/liter...
Hypothyroidism was defined as clinically significant if TSH > 4.5 mIU/liter and T4 < 57.9 nmol/liter and as subclinical or mild when TSH > 4.5 mIU/liter and T4 >= 57.9 nmol/liter...
Subclinical hypothyroidism was defined as having TSH levels ≥ 4.5 mIU/L and FT4 within the normal reference range [of 0.6-1.6 ng/dL]. Those who had TSH levels ≥ 4.5 mIU/L and FT4 below 0.6 ng/dL were defined as having clinical hypothyroidism.
Thyroxine (T4) has molecular weight 776.87 g/mol.
In adults, normal levels of total T4 range from 5–12 micrograms per deciliter (mcg/dl) of blood. Normal levels of free T4 range from 0.8–1.8 nanograms per deciliter (ng/dl) of blood.
I haven’t converted these densities to molarities, so I haven’t compared these ranges with those provided by the ’88-’94 paper, but this distinction seems relevant.
Good catch, I will edit the previous comment tomorrow when I’m on my computer. Given that the sub vs clinical distinction turns on T4/FT4 and these papers test for different values, I’d need to give more thought about how comparable they are.
Update: I have now looked into the raw TSH data from NHANES III (1988-1994) and compared it with data from the 2011-2012 NHANES. It seems that, although median TSH levels have increased a bit, the distribution of serum TSH levels in the general population aged 18-80 (including people with thyroid disorders) has gotten more concentrated around the middle; both very high levels (characteristic of clinical or subclinical hypothyroidism) and very low levels (characteristic of clinical or subclinical hyperthyroidism) are less common in the 2011-2012 NHANES compared to NHANES III. You can see the relevant table here. There might be bugs in my code affecting the conclusion of the analysis.
This paper, which pretty much used the same NHANES surveys, looked at a somewhat different thing (thyroid levels in a reference population without thyroid disorders or other exclusion criteria) but it seems to report the same finding w.r.t. high TSH levels: a lower proportion of the population in the latest survey meets the TSH criteria for clinical or subclinical hypothyroidism.
I’m a bit confused about this update. A lot of chronic diseases are very common. And as I showed, hypothyroidism has not been increasing over time. It might be decreasing. And, again, the geographical pattern of hypothyroidism does not match the geographical pattern of obesity.
I’m specifically considering subclinical hypothyroidism. From the paper you link:
If we’re working with the “lithium causes a desire to overeat and be sedentary (via hypothyroidism and possibly other mechanisms) in young people, which leads to lifelong obesity-promoting eating and activity habits” version of the hypothesis, then it may just be that Brazil and China are only now gaining the wealth and food supply to permit this to occur in a large enough swathe of the population. We see obesity growing exponentially in China and India (I couldn’t find a graph for Brazil), while it’s looking like it’s on the concave part of the sigmoid curve in the USA.
I’m inclined to think that if lithium is causing obesity in this manner, that subclinical hypothyroidism is one of its important mechanisms of action. If treating subclinical hypothyroidism in young people did not lead to long-term lower rates of obesity, I would lower my credence in an important dietary lithium-obesity link significantly.
The other paper I linked, which uses nationally representative data from the 2007-2012 NHANES, estimated the prevalence of subclinical hypothyroidism to be 3.5% (lower than the prevalence in the 1988-1994 NHANES, which was 4.3%), and noted that the prevalence of at-risk TSH levels seems to have decreased or remained stable with time. (Although mean TSH levels have increased.)
(I apologize for not having replied earlier — I was curious and wanted to check the raw NHANES data on TSH levels myself before replying to you, so I tried to, but found that parsing one of the datasets was too hard and ended up not doing it.)
[ETA: actually, the 4.3% number is based on a different definition of hypothyroidism. With regards to the definition used in the newer study (TSH > 4.5 mIU/L in the absence of clinical hypothyroidism), it says the following:
]
No worries, thank you for all the great research you’re doing.
The analysis of ’88-’94 data says:
The analysis of ’07-’12 data says:
So we see a 20% decrease in subclinical hypothyroidism (4.3% → 3.5%), but an 800% increase in clinical hypothyroidism (0.3% → 2.4%).
My original argument was based on prevalence in the population, not rate of change across time. If anything, given that (as these papers state), clinical hypothyroidism most definitely is associated with BMI, I think they lend support to the hypothyroidism/obesity explanation. Perhaps what we are seeing is a more rapid move in individual patients from subclinical to clinical hypothyroidism, as a result of the hypothesized lithium contamination. In affected patients, by the time the medical system catches it, it’s usually already clinical, whereas in the (postulated) less lithium-contaminated 80s, there was a longer period of time in the subclinical phase per patient when contact with the medical system could catch and diagnose subclinical hypothyroidism.
I will however make a couple meta notes:
a) I’m not putting as much time into this as you, so I’m worried I’m losing track of the details of the argument.
b) I’m trying to salvage the lithium theory because I don’t think it’s utterly destroyed by this data, not because I think it’s extremely likely.
So I generally just have to apologize if, on reflection, my overall argument here is full of incoherencies and inconsistencies. I’m forming my thoughts as I write these comments, and I expect to change my mind in the future—I’m just not sure in which direction.
The abstract of the paper analyzing ’88-’94 data says that they used a different definition of “subclinical hypothyroidism” than the definition that is commonly used today (I had edited my comment to reflect that a few seconds before you replied. I am so sorry for the error!!). Quoting from the paper:
So it seems that the prevalence of hypothyroidism was 4.6% in this survey, not 0.3%. So the prevalence of clinical hypothyroidism has decreased.
With regards to what we nowadays call subclinical hypothyroidism (TSH > 4.5 mIU/L in the absence of clinical hypothyroidism), the paper that analyses ’07-’12 data does say:
Note: I’m a little bit sick today, and it’s possible I made a mistake in my stoichiometry or in converting from math to reasoning. If so, I will happily stand corrected if anybody points out my error.
The change in terminology is just verbiage.
In fact, it appears they havenarrowedthe definition of both subclinical and clinical hypothyroidism in the newer paper. In light of how they changed the definitions, we should think that a definition-neutral rate of both subclinical and clinical hypothyroidism has gone up evenmorethan I’d described in my previous comment.Hypothyroidism is defined in part by lower-than-normal thyroxine (T4). In the earlier paper, T4 levels are defined as “clinical” that would be defined as “normal” or “subclinical” in the later paper. According to the definitions of the later paper, all “subclinical” patients in the earlier paper would have been considered “normal.”They switched from measuring bound + unbound thyroxine (T4) to free thyroxine (FT4) in the second paper. So the numbers aren’t directly comparable because they’re measuring the molecule in two different states the body. I don’t know whether we can do more than rely on the researchers’ implied claim that the definitions of normal vs. subclinical vs. clinical hypothyroidism remain comparable under the new definition.
Extracts and calculations for legibility:
’88-’94 paper:
Subclinical hypothyroidism: TSH > 4.5 mlU/L and T4 >= 57.9 nM
Clinical hypothyroidism: TSH > 4.5 mlU/L and T4 < 57.9 nM
’07-’12 paper:
Thyroxine (T4) has molecular weight 776.87 g/mol.
(.6 ng/dL) * (10 dL/L) * (1E-9g/ng) * (1 mol/776.87 g) *(1E9 nmol / mol) = 7.7 nmol/L = 7.7 nM.
Subclinical hypothyroidism: TSH >= 4.5 mlU/L and 7.7 nM ⇐ T4 ⇐ 20.5 nM
Clinical hypothyroidism: TSH >= 4.5 mlU/L and T4 < 7.7 nM
FT4 is not the same thing as T4. From Medical News Today:
I haven’t converted these densities to molarities, so I haven’t compared these ranges with those provided by the ’88-’94 paper, but this distinction seems relevant.
Good catch, I will edit the previous comment tomorrow when I’m on my computer. Given that the sub vs clinical distinction turns on T4/FT4 and these papers test for different values, I’d need to give more thought about how comparable they are.
Update: I have now looked into the raw TSH data from NHANES III (1988-1994) and compared it with data from the 2011-2012 NHANES. It seems that, although median TSH levels have increased a bit, the distribution of serum TSH levels in the general population aged 18-80 (including people with thyroid disorders) has gotten more concentrated around the middle; both very high levels (characteristic of clinical or subclinical hypothyroidism) and very low levels (characteristic of clinical or subclinical hyperthyroidism) are less common in the 2011-2012 NHANES compared to NHANES III. You can see the relevant table here. There might be bugs in my code affecting the conclusion of the analysis.
This paper, which pretty much used the same NHANES surveys, looked at a somewhat different thing (thyroid levels in a reference population without thyroid disorders or other exclusion criteria) but it seems to report the same finding w.r.t. high TSH levels: a lower proportion of the population in the latest survey meets the TSH criteria for clinical or subclinical hypothyroidism.