Home Hypothyroidism Treatment Policy in the U.S.: A Literature Review

Table of Contents

Today, many hypothyroidism sufferers are getting inconsistent answers and often denied needed treatment, although there is an apparently pervasive belief that overtreatment is a more important problem.  Why do these problems exist, both in terms of diagnosis and treatment approaches and of policy conflicts among various health authorities?  What does this imply about the broader issue of the quality of primary care at a time when "evidence-based medicine" policy, perhaps too hastily, is being implemented, in large part to reduce medical care costs by cutting back on screening for and on treatment of certain diseases? Will the lack of relevant randomized double-blind clinical trials turn the clock back for most hypothyroidism sufferers, i.e., those who have received the somewhat arbitrary diagnosis of "subclinical" hypothyroidism under Patient Affordable Care Act rules? 

I have made every effort to reference full-length versions of articles; however I have limited myself mostly to those available for free.  Unfortunately, that has meant relying mainly on abstracts in the case of articles published before about 2000.  I have made these distinctions in the References section and therefore cannot evaluate the results of those abstract-only articles critically in any way.  In some cases, I have quoted sections of what I thought was ambiguous text from these abstracts rather than trying to paraphrase it. NOTE: Some articles which were originally available for free to the public, apparently because they were written with NIH support, are now available only through publishers at a cost; I have not had a chance to designate all which of these articles this situation applies to. However, I have provided the dates on which all the full-length articles were available to me for free.

This essay, though heavily researched, does not follow the conventions of research publications by confining the writer's opinions to a discussion section.  I have made an effort, however, to distinguish my perceptions from the published observations and conclusions of others by indicating mine in green. In addition, the "Problem," "Neglected Areas of Study" and, of course, "Discussion" sections are all my opinion.

This paper is intended for an audience familiar with the basic terminology of biology, chemistry, algebra and statistics. However, I have set forth definitions of some concepts that are specifically important to this essay.

I have indicated technical terms in red, and the title of a section giving background information is shown in blue. Another section, covering thyroid physiology in depth, has a purple title. The other sections should be accessible to those from a variety of backgrounds.  Those wanting only a summary of this paper's point of view will find it in the Discussion section.

Donna Tucker has given this essay an excellent "big picture" critical review, and has given me helpful advice leading to a much-improved rewrite of the abstract.  I do not hold her responsible for any errors in this paper. Otherwise, no one has read it critically. Please let me know of any corrections you think it needs.

Disclaimer: I am not a physician and therefore cannot claim to give individualized recommendations. Please do not regard this paper as a source of advice for self-diagnosis or self-treatment. Most research findings reported in this document are based on statistics gathered from research involving small groups of people (or involving animals) by scientists and therefore might not apply to many individuals. In sum, this essay puts a bigger emphasis on asking questions than on providing answers.


The diagnosis and treatment of hypothyroidism has undergone many changes just in the last century as a result of improving technology, and, partly as a result, has been the subject of a great deal of controversy. Understanding thyroid structure and function, recognizing the crucial role of iodine deficiency in the development of the disease, controlling the amount of iodine in the diet and environment, and the development of high-quality assays to measure the degree of thyroid disease have made its management an arguably very precise science. However, new setbacks in the form of government involvement have eliminated routine screening for thyroid disease and are starting to limit treatment for patients whose disease severity is considered to be "subclinical," a term that scientists and many practicing physicians interpret differently, which is based on sparse research, and which, unfortunately, applies to most hypothyroidism sufferers. There seem to be several problems that are making effective hypothyroidism treatment somewhat incompatible with current medical treatment conventions: 1) although failing thyroid follicles can be observed via thyroid stimulating hormone (TSH) assays, the thyroid compensates by producing new follicles, i.e., by creating a goiter, which keeps the total thyroid hormone production within normal levels, making the patient's hypothyroidism merely "subclinical" unless that patient's TSH values are unusually high and/or the thyroid hormone levels are abnormally low; 2) because of the steadily decreasing error in TSH assays over a few decades, normal ("reference") TSH reference ranges have decreased equally steadily, making it difficult to perform meaningful randomized clinical trials demonstrating efficacy of the standard treatment, i.e., administration of replacement thyroid hormone, i.e., levothyroxine (T4); 3) many of its symptoms and signs are shared with other conditions, so that the TSH assay is crucial to obtaining a diagnosis, and even though its measurements (if properly done) are extremely accurate and precise, the precision of the normal range limits is unknown; doctors are typically comfortable with assuming they have more precision, while patients insist that there is really less; 4) An abnormally low T4 and/or T3, crucial in making the "overt" hypothyroidism diagnosis, is often caused by severe non-thyroid disease apparently over-burdening the thyroid and 5) a persistent misuse of a very basic mathematical concept: significant figures.  Although TSH levels have a now well-known daily cyclical pattern and are closely tied to the sleep-inducing hormone melatonin levels and to levels of stress, e.g., imposed by activity level according to some research, those levels are apparently considered to vary widely and randomly by some physicians, in their eyes reducing the value of measuring of TSH and calling into question the treatment of "subclinical" hypothyroidism with thyroid hormone replacement treatment in older patients. There is also a controversy over the treatment of "subclinical" hypothyroidism in pregnancy, which places special stress on the pregnant woman's thyroid during the first trimester, when the embryo's thyroid has not developed; varying experimental designs have led to equally various conclusions. In addition, the link between hypothyroidism and premenopause, when steadily dropping estradiol levels make homeostasis difficult to maintain, has apparently gotten little or no attention from researchers, while medical center and group practice advertisements indicate physicians' awareness of the problem. Recently, the linking of the findings of the advisory group, the U.S. Preventive Services Task Force (USPSTF), to decisions about mandatory insurance coverage by the Patient Protection and Affordable Care Act (ACA) has resulted in the elimination of screening for thyroid disease and apparently cutbacks in treatment of "subclinical" hypothyroidism in part because of an important discrepancy in the aims of these two bodies. In addition, the USPSTF's recommendation regarding the diagnosis and treatment of depression, which it identifies solely as a disease rather than a potential symptom of hypothyroidism and other diseases, has created the possibility of hypothyroidism sufferers receiving the standard treatments for depression, and only those. What we need, then, is a better-coordinated approach to patients with hypothyroidism aimed at understanding the whole problem, perhaps with fresh eyes, giving reduced weight to studies that include unproven assumptions in the starting points of their reasoning. The "settled" science necessary to diagnose and treat hypothyroidism sufferers, and indeed its art, is in place; what we need to do now is to clear away the social, political, and economic roadblocks to achieving this end.

The problem as stated by the authorities

Hypothyroidism, the condition of ailing performance by the thyroid gland, occupies a unique place in America's medical world.  It is common, especially in older people, has many distinctive clinical signs and symptoms, and is easily, cheaply, and safely treated, in striking contrast to hyperthyroidism and diabetes.  Standard diagnosis of primary hypothyroidism, i.e., disease that originates in the thyroid gland itself, according to current medical guidelines, usually involves one straightforward hormone level blood test. Standard treatment involves very infrequent monitoring, typically yearly, and treatment by one daily pill containing a single thyroid hormone according to these guidelines. There are currently no screening recommendations according to the U.S. Preventive Services Task Force, an advisory group reporting to Congress, although several professional physicians' organizations do offer them.

Yet many people, patients and physicians alike, criticize our medical care system for institutionalizing its underdiagnosis and undertreatment, even though a "mild" or "subclinical" level of this disease is now being implicated as a significant risk factor for heart disease and for non-alcoholic fatty liver disease, and, in the unborn children of affected women, birth defects and miscarriage.  According to Barnes (1976), Arem (1999), Shomon (2000), Brownstein (2013), and Gold (1987), hypothyroidism has persisted in being underdiagnosed because it is done on the basis of a single lab test, i.e., the thyroid stimulating hormone (TSH), without regard to clinical signs and symptoms.  Although the approaches they propose are varied and interesting, they seem to be in general agreement about the clinical manifestations of the disease: depression, pain, disability and increased susceptibility to the "major" diseases. What makes the situation especially difficult is that patient suffering is typically the first manifestation of the disease, while symptoms are regarded as having less and less validity as diagnostic criteria as the adoption of objective, easily measured criteria takes hold. In this way, hypothyroidism shares the basic problems of neurological and mental illness: the physiological sources of the pain and disability so characteristic of the disease are difficult to prove objectively.

O'Reilly (2000), a British clinical biochemist, observed the trends that make thyroid disease diagnosis especially difficult today.   He refers to the "remarkable downgrading of the clinical aspects of hypothyroidism and hyperthyroidism" in spite of the fact that "there are no data on the relative importance of biochemical thyroid function tests and clinical symptoms and signs in assessing thyroid dysfunction." He also points out that 1) the thyroid hormones triiodothyronine (T3) and thyroxine (T4) levels are not the only factors influencing thyroid stimulating hormone (TSH) levels and that 2) the relationship of patterns of TSH, T4 and T3 levels to health status in "systematic illness" is "poorly understood." This essay bears his perceptions out, and adds observations of how other forms of sometimes temporary stress, such as physical activity, sleep disturbance, drugs, other hormones, environmental poisons and nutritional deficiency (or excess, especially in the case of iodine) put stress on the thyroid, affecting these hormone levels in misleading ways. These factors can make diagnosis difficult by masking the condition in individuals or by contributing to the widening of normal ranges. As far as I know, the focus on TSH levels O'Reilly describes is the same in the U.S. today, and, because of this, it seems to me that any truly effective TSH level normal range standard would have to be based on statistically determined probabilities of the impact of these factors on the individual. This essay attempts to pin down which such statistics are available and how they are handled.

One source of confusion and disagreement is that the TSH assay has increased substantially over the last several decades with the improvement of supporting technology, which caused the accepted "reference range" to shrink by about half and the determination of the bottom of this range to become feasible.  Today, the error in a properly performed TSH assay is negligible, removing a great deal of pressure on hypothyroid patients to give convincing accounts of their symptoms.  However, physicians have apparently accepted the new ranges at varying rates.

My biggest surprise was the discovery that these treatment issues do not arise from a lack of interest in and study of hypothyroidism on the part of the medical research community, even though the issue receives practically no major media coverage.  On the contrary, this disease has been extensively studied, with mountains of detailed data produced, and many sweeping interventions, arguably too many, undertaken by the United States government in the twentieth century.  Our knowledge of the thyroid is actually rather lopsided: although we know a great deal about the physiology of thyroid hormone production and biochemical activity, we have only a hazy understanding of how thyroid hormones give us that subjective feeling of having more energy, of being alert enough to think more quickly and accurately, being able to digest our food rapidly and completely, and so on, and of where to draw the line when there is a problem in these areas.

Perhaps part of the problem is that the dramatic reduction of iodine deficiency, and later on, of iodine excess, has caused public attention to shift away from the disease.  Large goiters are no longer seen as the main manifestation of hypothyroidism; today, weight gain, hair loss, and neuropsychiatric changes have gained informal recognition as the earliest signs of the disease, even though they play only a minor role in its formal diagnosis.  On the other hand, Americans are far healthier on the average than they used to be a few decades ago, rarely dying before age 60 of ischemic cardiac disease and having much higher IQs. Therefore, what used to be seen as subtle problems constitute significant handicaps for some individuals today. This issue has been better recognized in western Europe than in the U.S.

Current medical guidelines (recommendations) for screening, diagnosis and treatment of hypothyroidism

When two elephants fight, it's the grass that suffers.

-African proverb

All of the below recommendations were put forth by Garber et al., (2012), except when specified otherwise. All were mentioned in this article.

Patients with abnormally low "free" T4 levels and/or TSH levels of 10 mIU/L or higher should be treated with supplemental levothyroxine.  The normal ("reference") range to be used for TSH is 0.45-4.12 mIU/L if local laboratory normal ranges are not available. Treatment with levothyroxine should be considered if the TSH is between 4.12 and 10 mIU/L and the patient reports certain symptoms, has anti-thyroid peroxidase antibodies, and/or has atherosclerosis or risk factors for that condition, presumably "bad" blood lipid levels, while a TSH over 10 mIU/L should be a strong indicator for treatment, because of an "increased risk of heart failure or cardiovascular mortality" (p. 1012).  Pregnant women should get similar consideration if their TSH is as low as 2.5 mIU/L (first trimester), 3.0 mIU/L (second trimester) or 3.5 mIU/L (third trimester). 

But what about clinical signs and symptoms of hypothyroidism, i.e., those discovered via a hands-on exam by a physician or reported by a patient? This document dismisses "several rating scales" of their relationship to the severity of the disease as having "low sensitivity and specificity," in essence saying that they are poor indicators of either the presence of absence of hypothyroidism in particular. However, it grants some apparent validity to "ankle reflex relaxation time," though it dismisses it as "a measure rarely used in current clinical practice" (p. 998). An exception to this rule, however, is made in the case of "nonexperimental, clinically obvious, evidence" such as "myxedema coma" (Table 2).

And what about iodine deficiency? "Iodine supplementation, including kelp or other iodine-containing functional foods, should not be used in iodine-sufficient areas" (p. 1016).

The AACE recommends that "older patients, especially women, should be screened" and that screening should also be applied to patients diagnosed with certain other diseases or having a family history of thyroid disease. Several other physicians' associations, i.e., the American Thyroid Association, the American College of Physicians, and the American College of Family Physicians, recommend screening of patients over a certain age (ranging from 35 to 60) and all but one, the American College of Physicians, recommend screening in men as well as in women.

It is worth noting that none of these groups suggested that body-mass index (BMI) should be used as a diagnostic criterion.

The U.S. Preventive Services Task Force (USPSTF) concluded that "current evidence is insufficient to assess the balance of benefits and harms of screening for thyroid dysfunction in nonpregnant, asymptomatic (my emphasis) adults." (LeFevre, 2015). This task force assigns its "statement an "I" value, meaning that it lacks the information it needs either to recommend or recommend against screening for thyroid disease. The paper itself attacked the endocrinology establishment for having a fundamentally flawed methodology for diagnosing thyroid disease and for not having conducted clinical trials evaluating symptoms as well as signs to determine treatment approaches.

The USPSTF also accused this group of having too much internal disagreement about where the top level of the TSH normal range should be, claiming that the only limit that they achieved consensus about was 10 mIU/L. Actually, the factual basis of this statement is questionable: the upper limit of the currently proposed TSH normal range, including even European research, is much lower, at about 2.5-4.5 (as this essay will discuss later), so there is indeed physician consensus that the trouble starts at a considerably lower TSH level.

The USPSTF defines "subclinical hypothyroidism" as "an asymptomatic condition in which a patient has a serum thyroid-stimulating hormone (TSH) level exceeding the upper threshold of a specificied laboratory reference interval (commonly but arbitrarily defined as 4.5 mI/UL) but a normal thyroxine (T4) level" (LeFevre, 2015).

A prominent endocrinologist soon afterward expressed her disappointment, attributing their conclusion to "largely to an absence of clear guidance from randomized clinical trials as to the balance of benefits and risks of treatment of subclinical or preclinical disease" (Manson, 2015). She expressed support for "aggressive case-finding and targeting high-risk groups for thyroid dysfunction," consistent with the policies of the physicians' groups mentioned above and the hope that the USPSTF would eventually be able to provide "clear guidance." The American Thyroid Association, which recommends screening every five years beginning at age 35, might have based its findings on a cost-benefit analysis using the general population's quality-adjusted life years (QALY) as a criterion (Danese et al., 1996).

A recent USPSTF recommendation statement regarding depression screening (January 2016) presented new potential problems for those with undiagnosed but symptomatic thyroid disease because it assumes that depression 1) is not associated with any other diseases, 2) can be diagnosed reliably with a questionnaire alone (awarded a "B" grade, therefore recommended), and 3) should be treated only with antidepressants and/or cognitive-behavioral therapy. This puts undiagnosed hypothyroidism patients with depression symptoms at risk for being treated with antidepressants instead of thyroid hormone replacement. I have discussed this matter in detail elsewhere (Pugh, 2016).

According to a new report from the USPSTF (December 2016), thyroid screening was not listed among the "high-priority" preventive services which require further research.

One indicator of a new hands-off approach to mild hypothyroidism is a recent article describing the treatment of a 62-year-old patient in the JAMA Diagnostic Test Interpretation section (Papaleontiou and Cappola, 2016). This patient, who presented with a TSH of 4.88 mIU/L and showed two symptoms of hypothyroidism, i.e., hair thinning (and "itchy scalp") and cold sensitivity, was given an apparently tentative diagnosis of subclinical hypothyroidism on the basis of her mildly elevated TSH. Her T4 was not measured because her below-10 mIU/L TSH was considered sufficient to rule out overt hypothyroidism. The authors did treat her, apparently because of her symptoms, although they expressed skepticism that those symptoms were related to a thyroid problem. When treatment with 25 mcg of levothyroxine (daily) had reduced the patient's TSH level to 2.75 mIU/L, researchers ordered an antibody (TPOAb) test, and on the basis of normal results on the latter and the patient's reported improvement in her symptoms, took the patient off the medication. Although the patient's TSH scores rose again on the average, her symptoms reportedly went away. The authors apparently assumed that the patient had no non-thyroidal illness that might have caused a subnormal T4 result, and the continuing absence of symptoms when the patient's TSH went up to 5.14 mIU/L four months later did not appear to jog their curiosity. The authors say that "mild TSH elevations ... may be a normal manifestation of aging." What remains a mystery is how the patient came across in general: Did she manifest a normal energy level? Was she a submissive patient referred for a consultation by a primary care physician? Did she feel financial pressures to go off the medication and make her visits to the physician as infrequent as possible? Another concern is the authors' assumption that TSH levels "fluctuate" wildly and apparently unpredictably, implying that mild hypothyroidism is usually a temporary condition, although the relevant literature does not appear to support this point of view; the time of day appears to be the main factor influencing TSH levels, in turn because it is related to short-term stress levels, as studies by Van Reeth et al.(1994), Leproult et al. (1997), Scheen et al. (1998), and Buxton et al.(2000) suggest; this is discussed in a later section.

Another case study which reflects this newly skeptical attitude toward treating "subclinical" hypothyroidism, especially in "elderly" individuals (Portillo-Sanchez et al., 2016), involves a 72-year-old patient with "coronary heart disease" and "type 2 diabetes," with a high (7.2 mIU/L) TSH and a normal (1.3 ng/dL) T4. He was started on 75 mcg of levothyroxine daily, which was high according to Drugs.com (a site managed by several registered pharmacists), which recommends the starting dose for hypothyroid individuals who are "elderly" and with "cardiac disease" to be from 12.5 to 25 mcg (https://www.drugs.com/dosage/synthroid.html). Perhaps it is no surprise, therefore, that this patient developed symptoms and signs of heart disease after a month of treatment, and that his TSH dropped to 0.1 mIU/L. At any rate, the authors decided that this patient should have never been treated for hypothyroidism, and expressed their belief that their experience treating him suggested that older patients should not be treated for hypothyroidism unless their TSH is higher than 7.5 or 8.5 (presumably "mIU/L," although they actually stated "IU/L"), while they also noted that TSH values above 5.5 mIU/L affected no more than 3% of the population. In fact, they concluded that "treatment of subclinical hypothyroidism in elderly patient is probably not worth the costs and potential downsides." To be entirely fair, the authors might have had patients without reported symptoms or obvious signs in mind, i.e., what "subclinical" seems more logically to mean; they might treat a future patient in obvious distress differently.

The American Association of Clinical Endocrinologists (AACE, 2017) has launched a year-long campaign to spread awareness of autoimmune illness, featuring Hashimoto's Disease, considered to be the main cause of hypothyroidism. This is especially timely considering the recent increase in responsibility for diagnosis on the patient, who needs to report symptoms in a convincing manner in order to receive treatment, since screening has been abandoned by many practitioners.

The real question: what does the thyroid do and how does it affect us in health and in disease?

Ask most people what they think the thyroid does, and (if they know anything about it) they are most likely to say it provides energy and that fatigue is the most common sign of a problem. Of course, there are also miscellaneous signs and symptoms that do not seem to be related to one another, e.g., weight gain, cold intolerance, loss of hair on the scalp and parts of the eyebrows, facial puffiness, thick and dry skin, slow and labored speech, depressed mood and cognitive problems. Trying to identify these patterns in an individual just by referring to a book can be very difficult for someone without related medical training.

Another typical explanation is that the thyroid regulates "metabolism" or "the rate of metabolism." The general impression is that thyroid hormones speed things up, burn calories faster, make thoughts flow faster and of course keep you warm. But these hormones are hardly unique in producing any single one of these effects.

What makes thyroid disease even more difficult to evaluate is that so many hormones and body systems are involved in making sure that this aspect of health is maintained, making definitive diagnosis of the disease  Generally speaking, overt hypothyroidism is diagnosed when TSH levels are elevated, i.e., above the normal range, and T4 and/or T3 levels are below the normal range. Subclinical hypothyroidism (SCH) is a term that suggests an absence of clinical signs and symptoms in spite of abnormal TSH blood test results but is in fact defined by many researchers to describe a particular range of (abnormally high) TSH values diagnostic of hypothyroidism, accompanied by normal T4 and T3 values, without regard to anything clinically observed; research subjects are apparently considered to be asymptomatic if they are not being treated with replacement hormone.  Its research and individual medical meaning may vary: although the practicing physician Wu (2000) includes clinical signs and symptoms suggesting thyroid disease in the definition of this condition, researchers in general apparently do not. Criterion TSH values vary widely, and there is a good deal of controversy about its medical importance and whether it should be treated.

In fact, thyroid hormones influence (both thermal and chemical) energy production and body tissue maintenance, and indirectly (via melatonin) induce sleepiness in individuals running low on energy (which we do at the end of each day). This essay will attempt to explain what cellular processes the thyroid hormones influence, how the body produces these hormones and how problems in these processes manifest themselves as thyroid disease.

Explanation of some basic scientific terms and practices: a crash course

NOTE: You do not have to read this section to understand the major points that this paper makes.  However, you do have to understand the concepts listed here to read much of it critically.


Metabolism is typically defined as all the chemical reactions going on in the body. In the context of thyroid physiology, this boils down to 1) growth and repair of tissue and 2) energy production. A metabolic pathway is a chain of such reactions leading to results that support life (ideally).

Hormones and neurotransmitters

Hormones are a structurally diverse set of chemical messengers that travel through the blood; only very small amounts of each are necessary to trigger a cascade of metabolic activity, which they do by "docking" with receptors in target cells. Endocrine glands, such as the thyroid, produce some hormones and send them into the blood, in which they can travel anywhere in the body.

In the system controlling thyroid activity, the hypothalamus acts a switchboard, receiving input from appetite-controlling hormones located in the stomach, intestines and fat cells and producing hormones that influence the rate of production and destruction of cells throughout the body in concert with available nutrients.

Neurotransmitters (first messengers) link to a receptor in the cell membrane, which activates a second messenger inside the cell  in the setting of this paper, the diacylglycerol metabolic pathway, which leads to the passage of calcium ions through the cell membrane, much as occurs in nervous system function. In contrast to "pure" endocrine hormones, they have a very local function, affecting a series of adjacent cells.   In plain English: picture the neurotransmitter as a person knocking at a door (the cell membrane). Someone inside (the second messenger) accepts the message without opening the door, and goes away to deliver the message to those inside the building, and to those in neighboring buildings. In this case, the message allows other people (calcium ions) to enter those buildings.

However, recent evidence suggests that estradiol, an estrogen, acts as a neurotransmitter in the hypothalamus (Qiu et al., 2003).

Of course, the endocrine hormones, produced by endocrine glands, i.e., TSH, T3 and T4, are discussed here, as well as those in the growth hormone cascade. Several other hormones are produced by tissue cells, i.e., the stomach, intestines, ovaries, pancreas beta cells and fat cells. Estradiol, an estrogen, is examined in many studies referred to below; researchers often refer to it as "E2." These hormones also travel through the blood to their destinations. These relationships are shown in Fig. 1.

Iodine, other halogens and molecules with similar behavior

Iodine (I), bromine (Br), chlorine (Cl) and fluorine (F) (as well as astatine) are members of the halogen group on the periodic table, which have seven electrons in their valence, or outer electron shell; as a result, their chemical behavior is very similar and they have a strong tendency to compete with each other in bonding. The maximum number of electrons in this valence is eight; when the valence is filled, i.e., all eight electrons are present, the particular atom or ion (its state when the halogen takes an electron from another atom) has its lowest tendency to react, i.e., electronegativity. On the other hand, halogens in their elemental rather than ionic form have the highest electronegativity of all groups and as a result are rarely found in nature. Halogens usually exist as ions, known as halides, e.g., I-, or in molecular form, either as bonded pairs of the same halogen, i.e., I2, or bonded with other atoms.  When researchers refer to "inorganic iodine," they usually mean I- (iodide ions) and/or I2 (molecular iodine). "Organic iodine" typically describes iodine atoms that are constituents of hormones and enzymes.

A halide, which has a filled valence, has a charge of -1, i.e., its number of protons minus its number of electrons, which causes it to be attracted to ions with a +1 charge by this same arithmetic.  In this respect, it also behaves similarly to ions with the same -1 charge, such as perchlorate ions (ClO4-).  The significance of all of this is that iodide ions can be displaced by certain other such similar ions, which is rarely if ever desirable and sometimes problematic.

The larger atoms in the same group, in this case, halogens, hold electrons in their valences with less force than smaller atoms because their electrons are farther from their nuclei. Therefore, an iodide ion, for instance, is more likely to be detached from the molecule it is bonded to than are fluorine, chlorine or bromine atoms. This implies that iodine is readily displaced in molecules such as T4 by these other halogens.

Iodide and chloride ions are considered to be essential nutrients; bromide ions are not.  Fluoride ions are not true nutrients, and though their use in public water supplies to prevent cavities is generally accepted, there is some controversy. Iodide ions are highly water-soluble, and they are the most common form that iodine takes in the environment and in the body. Most of the iodine in the body is used in the thyroid gland, but it is also found in other parts of the body.

Water-soluble vs. fat-soluble molecules (or polar vs. nonpolar molecules)

You've heard the old saying, "Oil and water don't mix." What makes certain types of molecules draw closer to one another (the essence of mixing) and others keep their distance? The difference is the presence or absence of mild electrical charges in these molecules, which act sort of like magnetism. Oils, in fact the lipids of which they are a subset, are nonpolar, i.e., they do not have any such electrical charge, so they can lie right next to one another without interference. On the other hand, water is an example of a polar molecule. It carries a small charge because it has a relatively large molecule (oxygen) that pulls electrons a little distance away from the nuclei of the hydrogen atoms that it is bonded to; as a result, the oxygen atom has a slightly negative charge and the hydrogen atoms each a slightly positive charge. So the oxygen atom in one water molecule is attracted to one of the hydrogen atoms in a neighboring water molecule. This is what gives water its surface tension.

The scientific literature typically refers to water-soluble (polar) substances as hydrophilic and fat-soluble (nonpolar) substances as hydrophobic.

Not all types of molecules are completely hydrophilic or hydrophobic; some have a hydrophilic part and a hydrophobic part. Tyrosine is such a case: its phenyl group, i.e., six-carbon ring, is hydrophobic, while its side chain (-OH) is hydrophilic. This means that it can show both types of behavior, apparently: it can be carried along by water molecules attracting its hydrophilic side chain, but the hydrophobic phenyl group allows (probably most of) it to pass through the cell membrane of the thyrocyte through passive transport, defined just below.

The cell cycle: how the body grows

Living cells each are in one of three basic states at any given time: growth (increase in size), division into two cells (mitosis) and rest.  The cell cycle begins with growth (G1 and S) and ends with mitosis. Growth takes place in two stages, the first (G1) before DNA synthesis (S) and the second (G2). The many steps involved in this cycle are regulated by cyclins, which in turn bind with the enzymes cyclin-dependent kinases (CDK) to form cyclin-dependent kinase complexes, determining which substrates these enzymes will react with. They regulate the cell cycle by determining whether the cell is progressing through the cycle properly, either by giving go-ahead signals if so or by causing programmed destruction (apoptosis) if the process goes wrong. Insulin-like Growth Factor 1 (IGF-1) stimulates the (gene) expression of cyclins D1 and E; cyclin E regulates the G1-to-S phase transition in the cell while D1 regulates G1 (Mairet-Coello et al., 2009, Borowiec et al., 2011). Cyclin A2, on the other hand, responds to DNA damage of the cell in either of two ways based on its timing: 1) before gene transcription/DNA synthesis, to trigger apoptosis, or 2) after gene transcription/DNA synthesis, to repair the DNA damage instead (Finkielstein et al., 2002).

The take-home message here: IGF-1 stimulates cell repair and proliferation, but not apoptosis. (There are certain fail-safe body mechanisms in healthy people that keep IGF-1 from causing cancer, but this paper will not explore this.) It works closely with thyroid hormones, as shown below.

Transport of substances into the cell

There are two basic ways a small molecule or ion can get into the cell by passing through the cell membrane: 1) by passive transport, i.e., done only by physical rather than chemical energy and 2) by active transport, which involves the use of chemical energy. Fat-soluble (actually, lipid-soluble) molecules, i.e., those with no electrical charge ("nonpolar"), can enter through passive transport. But the more asymmetrical water-soluble ("polar") molecules and ions need active transport to be pulled through the cell membrane, and this is done with a transmembrane protein (ion transporter) which uses electrochemical energy to perform active transport on the ions. 

In the case of a symporter, which is a type of transporter which brings in two types of ions, the protein's receptors capture one type of ion, pulling these inside the cell, creating an electrical charge which pulls the other ion with it. Other ions which can be pulled into the cell in place of another by the symporter are called competitive inhibitors. The relative strength of this pulling force cannot be easily predicted by an ion's structure, although each symporter seems to operate only on pairs of ions with the same electrical charge.

Very large molecules, such as many proteins, enter and exit cells through endocytosis and exocytosis, which are wonders of topology. As they push up against the cell membrane of a cell, the membrane folds inward and that part breaks away from the cell's membrane to enclose the protein. So in a sense the protein (or other large molecule) remains outside the cell while being enclosed in it; this enclosure is known as a vesicle.  Of course, this limits the types of interactions this large molecule can have with the cell.

How cellular data are obtained and analyzed in the laboratory, especially as applied to TSH measurement

The studies discussed here involve tests for concentrations of hormones (especially TSH, T4 and T3) and other substances in the blood and in the tissues.  The concentrations of very small molecules are measured via radioimmunoassay (RIA) or by enzyme-linked immunosorbent assay (ELISA), a new non-radioactive alternative.  These assays have increased steadily greatly in precision since the 1950s, affecting methods used to determine the limits of normal ranges for these hormones greatly, and therefore the values of these limits.  Because the lower limits of normal ranges are smaller than their upper limits, they have required greater precision on the part of these assays to be measured meaningfully, and have been established later than the upper limits.  These upper limits have decreased in part because the margin of error has been reduced, making overdosing with replacement hormone based on measurement errors less likely.

On the other hand, detection of and measurement of the levels of proteins, especially in tissue cells, involves another approach that draws on epigenetics, the study of gene expression, i.e., the "turning on" or "turning off" certain genes as the result of chemical triggers.  Certain molecules known as transcription factors (in the case of this essay, mainly hormones) cause this turning on by binding to a response element, i.e., an expression target segment of DNA of a molecule, creating messenger RNA, which in turns signals ribosomes to create characteristic proteins known as peptides, strings of amino acids which form tissue, enzymes and various other molecules necessary for life processes.  Transcription factors "unzip" DNA at particular points, allowing nearby matching nucleotides to join those of the DNA, forming the messenger RNA. Isolating and identifying this messenger RNA is the key to determining which proteins are created within the cell.  Chromosomes in some individuals have more copies of a particular gene than those of other individuals, making it possible to produce more of those genes' corresponding proteins.  Research papers refer to "turning on" some or all copies of genes as up-regulating those genes and to "turning off" gene copies as down-regulating that gene.

Inflammation and cytokines, and their experimental stimulation

Inflammation is the body's healing process in response to infection or injury. Inflammation consists of two basic functions: 1) repair of damaged tissue, involving blood clotting and tissue regeneration and 2) identification of and destruction of non-nutrient foreign molecules and damaged body cells.  The latter consists of the immune system, composed of two basic parts: antibodies (sometimes called B-cells) and T-cells (a type of lymphocyte, in turn a type of white blood cell) and of macrophages, drawn to the scene of attack by chemotaxis (as though responding to an irresistable smell) and which "digest" unwanted molecules. Antibodies identify problem substances, usually foreign matter and body cells that have been damaged too much; they do this by examining the shape of molecules and comparing that to their library of acceptable shapes. If the molecule "flunks" the test, the antibody marks it for destruction and T-cells it comes in contact with destroy marked cells by breaching them.

This process is mediated by cytokines, chemical messengers produced by T cells and various other cells that allow the immune system to communicate with the endocrine and nervous systems; the introduction of antigens (large non-nutrient foreign molecules, usually proteins or polysaccharides) trigger their appearance via interaction with antibodies.  Shape recognition (correct or not!) by "blind" antibodies is the basis of this process: antibodies match a particular part of the surface of an antigen called an epitope with a "memorized" shape, and mark the antigen for attack.  Perhaps because this decision is made on the basis of such a small area, error is more likely with larger molecules.  Two large molecules performing key functions inside the thyroid are typical targets for antibody attacks that can lead to hypothyroidism: thyroid peroxidase (TPO) and thyroglobulin (Tg).  On the other hand, Grave's disease is caused by an antibody which mimics TSH, increasing the stimulation of TSH receptors, in turn causing hyperthyroidism.

A hapten is a small molecule that tricks antibodies into making the wrong judgment about whether to attack a particular molecule; it acts by attaching itself to the surface of such a molecule, altering its apparent shape. Haptens are designed and used by experimenters to trigger autoimmune responses in (usually animal) subjects, but apparently exist in nature too.

Lipopolysaccharide (LPS), a large molecule that is found on the exterior surface of gram-negative bacteria cell membranes, is commonly used experimentally in animal studies as an antigen to stimulate the creation of cytokines, triggering an immune system response.

Freund's adjuvant, which comes in two forms, is used for a similar purpose; its complete form contains dried, i.e., killed, mycobacteria in a water-and-oil emulsion, while the incomplete form just contains the water and oil. It acts as a hapten; experimenters use it to trigger an autoimmune response in animal subjects to large molecules such as thyroglobulin normally found in these animals' bodies.

Erythrocyte sedimentation rate (ESR) is a blood test used to measure the amount of inflammation in the body. It is a low-budget but less effective alternative to the RIA as a measure of anti-thyroid antibody presence.

Sometimes the inflammation process can go wrong. Sometimes it can choose to repair when attack is appropriate, as in the case of cancer or atherosclerosis.  When the opposite occurs, it is called autoimmunity.  Sometimes, apparently, both problems can occur together and this may even be typical. Could it be that parts of the body that persistently need repair somehow eventually draw the attack response instead?  If so, could thyroid tissue severely damaged by either too much or too little iodine, draw this attack response by having its shape, as detected by antibodies, change?  And are there more haptens in the environment today because of contamination of food by new, industrially produced chemicals? On the other hand, can autoimmune disease be brought on by infection in neighboring tissue, or even in other parts of the body, by mistakes the immune system makes in fighting that infection?  Can a throat infection cause thyroid tissue be targeted for attack? Is thyroid tissue especially vulnerable to antibody attack, especially its chemicals, TPO and Tg, and if so why?  We do know that large, complex molecules are mostly likely to become antibody targets.

Deep reasoning vs. shallow reasoning: appropriate in different situations

Deep reasoning is used to understand all relevant cause-effect relationships and is essential for the design of complex fail-safe systems.  Shallow reasoning, on the other hand, uses pattern recognition to identify familiar situations by their superficial manifestations. To make a crude generalization, deep reasoning is important to science, while shallow reasoning's efficiency makes it very useful in routine practice.

Negative and positive feedback systems and homeostasis

A positive feedback system is basically a vicious spiral: every stimulus drives the system more out of whack.  A negative feedback system is a self-correcting one; when something goes wrong, the system responds by reversing the effects of any stimulus. Homeostasis is a state of physiological stability necessary for health, maintained by a negative feedback system: it is manifested, for instance, by blood test values that stay inside their respective normal ranges with no overall upward or downward trend.

Significant figures

Our measurement instruments are inevitably limited in their precision, so we need a shorthand to indicate the limits of their measurement.  This is indicated by the number of nonzero digits in a number representing that measurement.  For example, "5.5," which has two significant figures, indicates that the value it represents to can be anywhere from exactly 5 to exactly 6. On the other hand, "10" has only one significant figure and represents a value known to be somewhere between exactly 5 and exactly 15.

Statistical models

A model is a usually simplified representation of something in the real world, retaining only its most important features and showing their relationships. It can be static or dynamic. A mathematical model can be a simple formula, e.g., F = ma (force = mass x acceleration); some people refer to that type of model as "plug and crank" or deterministic because there's only one possible value ("the answer") for F given two particular values for m and a. On the other hand, m and a can assume any positive values because that's the way the natural world operates, at least as described by the branch of physics known as "mechanics."

A statistical model, on the other hand, is much more complex: while this is not the place to give this a rigorous definition, the "answer" is a "best" fit rather than a particular number, and you, the model developer, make certain judgment calls about what variables to use and how much weight to give to each one. In the simple formula given above, mass and acceleration always get equal weight, but not in the world of statistics, especially as applied to biology. People live only so long; their TSH values cluster in a narrow range (mostly); they can only be male or female (at least the way clinical research is run today!), and so on. Also, you do not have an infinite number of possibilities; you are often working with a limited sample, the number of subjects in your study. Finally, you may not be able to pick the right variables for the model because you are not in a position to conduct all of the experiments you need to get all of the information you need. So you are in essence gambling, and having to take the best calculated risk.

Continuous vs. discrete variables

A continuous variable has an infinite range of possible values, e.g., temperature or time interval.  A discrete variable can have one of a fixed, usually small, number of values, e.g., a test result that is either positive or negative.  Discrete variables are also known as categorical variables because they often represent assignment to categories.  Continuous variables are typically representations of natural phenomena, such as certain blood test results; discrete variables are typically created by the experimenter and given values on the basis of the values of continuous variables associated with experimental subjects.

It is important to realize that cutpoints, dividing values between categories, contain very little information in themselves. They are often chosen arbitrarily, apparently because they are round numbers; 10, 100 and 200 are especially popular (and note that each has only one significant figure).  For example, just because a study concludes that, in general, subjects with variable values above a certain cutpoint are doing well in some way in contrast with those below it based on a categorical statistical model does not mean that all of the subjects with values above that cutpoint are doing well; it simply means that higher values for that particular variable indicate a better chance of the subject's doing well, and that the cutpoint value is included among the values of the subjects in the study (and is ideally in the middle of them).

Dependent vs. independent variables

In the simplest sense, the dependent variable (in a sense, the "answer") goes on the left side of the equation, and the independent ones on the right side. Generally speaking, the independent variables should represent causes and the dependent variable their effect. Ideally, you can control the values of the independent variables by selecting characteristics in your subjects that follow certain patterns.

"Real" vs. surrogate variables

Sometimes the most meaningful choice of a dependent variable, e.g., time to first heart attack, is not feasible to use in a model, and an easier-to-measure surrogate variable, e.g., a blood lipid measurement, is used instead. It is usually has been proven to be a strong predictor of the values in the variable it replaces, but sometimes without a full understanding of the causal relationship between them. Surrogate variables are more often referred to as risk factors.

Observational studies, clinical trials, and meta-analyses

Observational cohort studies gather data about human subjects without imposing any changes on their lives, but are still designed to identify factors associated with certain medical problems, although they cannot determine causal relationships. The subjects are not divided into treatment groups, but grouped into cohorts for analysis purposes according to whether they have the medical problem in question or are "normal." Researchers also gather certain types of subject information such as age, gender and health status data such as smoking history, blood pressure and lab test results and represent them as variables expressed in a statistical model. These studies are often done under the direction of and with the funding of the federal government in order to formulate recommendations to the public. Longitudinal observational studies, i.e., those that work with data gathered over a certain time period, are either retrospective, i.e., analyzing data that is already available, or prospective, i.e., gathering the data after the start of the study. On the other hand, cross-sectional studies work with data that has been gathered at only one timepoint. One disadvantage of retrospective observational studies with respect to clinical trials and prospective observational studies is that they do not always provide data for the variables necessary to answer the questions the studies seek to answer, and that the variables used are often only those easy to measure and which are less likely to require "soft" thinking. On the other hand, these studies cost less and involve less risk to the subjects. In addition, observational studies cannot prove cause-effect relationships among variables, although they can suggest those relationships by the magnitude of their correlation: pairs highly correlated variables are more likely to indicate that one cause the other, or that they are both effects of the same cause. On the other hand, it is probably safe to assume that poorly correlated variable pairs have no causal relationship, which can be helpful in the design of a later relevant clinical trial.

A clinical trial is an experiment involving human subjects designed to determine whether a cause-effect relationship exists between a candidate treatment and the health of these subjects. It involves an intervention, such as administration of a study drug, in order to see whether it reduces certain medical problems in the subjects that the study drug was designed to treat (or causes other problems).  The subjects (typically referred to as "patients"), who all have the condition that the study drug was designed to treat, are divided into treatment groups, made as similar as possible to one another in relevant ways by a (rather misleadingly termed) randomization process to maximize the probability that outcome differences among the treatment groups are caused only by the intervention; at least one group receives the study drug, for example, while one group receives a placebo, which is chemically inactive but has the same appearance as the study drug.  Statisticians use inferential statistics (see below) to assess the study drug's performance with respect to the treatment groups mainly by evaluating the change from baseline in key safety and efficacy parameters, known as clinical endpoints; the identity of the subjects is withheld from them, making the trial "blinded."  Usually the results of a clinical trial, if they are positive, result in prompt action, such as a New Drug Application (NDA) submitted to the FDA for permission to market the study drug. Many patients enrolled in these trials drop out, often because of illness; the FDA requires NDAs to provide a patient disposition, showing how many patients made it to each stage of the trial, and reasons for dropping out.

Ethical considerations limit the information available to clinical trials; ethical rules the exposure of subjects being exposed to known sources of harm in these studies.  For example, clinical trials designed to measure the amount of harm done by smoking on subjects would not be allowed because of strong existing evidence that smoking is harmful.  This issue has caused special problems recently because of the new approach that evidence-based medicine has taken: while in the past, clinical trials were confined to evaluation of new treatments or of those known to be especially risky and/or expensive, they have almost overnight come to be regarded as the only method to justify any kind of treatment, no matter how simple, safe, inexpensive, well-understood, or well-accepted it has been in the past.  In fact, this new emphasis runs the risk of eliminating the safest diagnostic and treatment procedures from standard practice because little or no need had been perceived in the past to call for clinical trials to test them, and perhaps in fact it seemed unethical to withdraw treatment believed to be necessary from subjects in order to test its efficacy.

Meta-analyses bring together data from selected small studies and treat the "final" calculations (effects), e.g., p-values or odds ratios, from each as though they were data points from one large study; a measure of heterogeneity, the variation in the results ("effects") among the studies is the other basic value taken.  The greater the heterogeneity, the less certain the calculation of the effect.  As Serghiou and Goodman (2019) put it in their explanation of how it is used, meta-analysis is "a foundational tool for evidence-based medicine."   However, because of the amount of subjectivity involved, most notably in the selection of the studies and assignment of weights, it is a subject of great controversy, especially where there are political implications.

Statistical nitty-gritty: how the p-value is derived and how it is, rightly and (sometimes) wrongly, used

The p-value is a statistically derived entity on which rests the conclusion of a typical study.  According to Wasserstein and Lazar (2016) in an official statement representing the views of the American Statistical Association, a p-value "is the probability under a specified statistical model that a statistical summary of the data ... would be equal to or more extreme than its observed value."  In the same paper they wrote, "Scientific conclusions and business or policy decisions should not be based only on whether a p-value passes a specific threshold."  Yet is this what in effect the application of evidence-based medicine is doing to public healthcare policy? Are we changing public medical care policy by using statistics in a way that the statistics profession believes is wrong?

The median is the value at the 50th percentile.  The mode is the most common value. Their average (also known as arithmetic mean or just mean) is a more familiar statistic: the sum of all the data values divided by their count. Their standard deviation (and its square, the variance) is a measure of variation in the data, i.e., how on the average they differ from that mean.

If the mean of of a data sample is close to that of the population from which it was collected, e.g., everyone in the U.S. or all the patients who have used a certain lab to get blood tests, the measurement result is said to be accurate.  If the variation in such a measurement is small, this measurement process is said to be precise.  Sometimes we do not have enough information about a population to determine a sample's accuracy, but we can measure its precision.  We see this issue later in the assays of hormone concentrations: it took researchers decades to get these assays' precision to be great enough to be useful in determining normal ranges for thyroid hormones.

Inferential statistics compare two data samples or a data sample and a population by using their means and variation measures (usually a particular measure, standard deviation).  In a nutshell, this comparison is a measure of the proportion of the distribution of their values that overlap. If there is no overlap, their p-value is zero; if there is a complete overlap, their p-value is one. The desired p-value varies greatly according to context.  If one is testing a study drug in a clinical trial, that drug might be considered a success if a comparison of the efficacy of the drug (perhaps cure rate) not only showed the better mean for the group receiving the drug, but also resulted in a small p-value.  But you would also expect many safety measures between a study drug group and a placebo group to be essentially the same, e.g., heart health for a study drug treating a minor cosmetic problem, and that would mean similar averages and a large p-value.

The standard interpretation of the p-value in practical terms is that it is the chance of there being no difference between the two variables being compared.  For example, a p-value of 0.05 in a clinical trial testing the efficacy of a study drug means that there would be a 5% chance that the drug is no different than the placebo.  Today, this is considered an unacceptably low value in such trials, and the new cut-off value is currently under discussion.

It's important to remember that a p-value is a continuous entity, and decisions about cut-off values where statistical significance begins are inevitably somewhat arbitrary. If a p-value turns out to be, for example, 0.07, it might not be deemed "statistically significant," i.e., have enough predictive power to meet the study's particular criterion, but it would not be right to say, "There was no difference" between/among the groups being compared. If there were absolutely no difference between two such groups, i.e., that there would be a perfect overlap, the p-value would be exactly 1.  On the other hand, that 0.22 p-value would suggest that there is a 22% chance, not a 100% one, that there is no difference in the two variables.  While a study drug would be expected to have much more predictable efficacy to qualify for marketing approval, the same p-value would probably be too low in experiments involving two variables expected to be the same, i.e., where the ideal p-value would be exactly one.

An odds ratio is a ratio of p-values for two different variables relative to a benchmark variable, e.g., the resulting test result for a subject taking a placebo.  In some studies, the odds ratio is referred to as the hazard ratio.

Normal Ranges (technically referred to as "Reference Ranges")

Why are normal ranges called "reference ranges?" According to Brabant et al (2006), there is a conflict between those who believe that "normal" implies absolute health to some people and others who believe that "abnormal" implies the presence of problems requiring correction, and that therefore "these problems have been circumvented by the definition of 'reference' values, implicating (sic) that absolute health does not exist."  This suggests that the professionals who use these ranges feel uneasy applying them strictly in practice, and regard them more as guidelines than rules.  I think this is a special problem because the limits of reference ranges vary widely relative to the clinical signs and symptoms that are typically found with the disease: it is far more likely for patients feel ill when their values on some tests are close to one of the limits of the reference range for that test than it is for them to feel that way when their values for some other lab tests are well outside the reference range.

The determination of a "normal" range of a continuous test value involves both cut-and-dried mathematics and subjective physician judgment.  First, a normal patient population (usually local to the laboratory where a particular patient is tested) is defined, i.e., those who appear to be disease-free, presumably both on the basis of clinical signs and symptoms (indicators of disease either reported to or determined by physicians through direct examination) and (previous) lab test results.  If the values measured by the particular test follow what's called a t-distribution, i.e., the mean, median and (single) mode are the same or very similar, the limits of the normal range are set at two standard deviations from the mean of those values, which are at percentiles 2.5 and 97.5 in a "perfect" (bell-shaped) normal distribution, a particular type of t-distribution.  If the values follow another slightly different distribution, such as the very common log-normal distribution, in which the mean is greater than the median and mode, the data have to be transformed for the sake of analysis.  If they are fundamentally different from the normal distribution, e.g., the shape of their distribution (its curve) is bimodal, i.e., having two "humps," then transformation will not help and normal range calculations by the above method are basically meaningless, although they are sometimes still done.

One big problem with normal ranges is that they are in part dependent on other lab test results, even previous results for the same test, and error will be perpetuated or maybe even increased by an incorrect determination of the normal patient population if the normal range for those tests are too wide or narrow to begin with. 

How scientists minimize harm when they don't know everything: type I and II errors, sensitivity and specificity

Live as if you were to die tomorrow. Learn as if you were to live forever. (attributed to Mohandas Gandhi)

This saying seems to give contradictory advice, but it illustrates a standard approach of experimenters to containing potential problems: when in doubt, make the assumption most likely to do the lesser harm if wrong (or the greater good if right).  Sometimes it makes sense to make different assumptions about the same thing in different contexts, and it's standard practice for scientists for do this both in experimental design and in interpretation of results.  Unfortunately it often involves making difficult judgment calls and sometimes leads to controversial results.

A Type I error is a false positive result, e.g., a test result erroneously indicating the presence of a disease; a Type II error is a false negative result, e.g., a test result that fails to detect the presence of an existing disease.  When a physician wants to determine whether a patient needs treatment, s/he needs to consider 1) whether a relevant lab test is more likely to produce a Type I or Type II error and 2) whether giving the patient unneeded treatment (as the result of a Type I error) or withholding treatment from one who needs it (as the result of a Type II error) is worse.  (We must all be familiar with this issue when it comes to the controversies swirling around when to administer antibiotics.) Similar considerations apply to policy-making.  But when it comes to situations involving multiple diseases, such as deciding whether to risk hyperthyroidism in a patient by treating him/her for hypothyroidism, making the right decision is even more complex.

Sensitivity is the chance of not making a type II error; specificity is the chance of not making a type I error.

What does that L- mean? (and those fancy prefixes with the apostrophes?)

Sometimes a chemical is represented with an L- prefix, which distinguishes it from its R- counterpart.  L-thyroxine, for instance, is the mirror image of the molecule R-thyroxine, although they otherwise have the same structural relationships among their atoms.  However, their (bio)chemical activity is very different!  L-thyroxine is a hormone essential for life, while R-thyroxine is useless and may even be bad for you.  Its synthetic form is referred to as levothyroxine in the context of its use as a commercially available drug.

Actually, the full formal name of this molecule is (S)-2-amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoic acid, according to International Union of Pure and Applied Chemistry (IUPAC) naming conventions;  L-3,3',5,5'-tetraiodothyronine is a somewhat less formal term also used. These conventions are very useful in describing the structure of every conceivable molecule, showing exactly what branches off from where, but in the context of this essay, it's easier to explain things using common names (and better yet, abbreviations!) So, from here on out, there will be no hyphenated or numerical prefixes or, for that matter, apostrophes mentioned in molecule names in this piece, except for L-DOPA.

For the sake of simplicity, I will refer to these molecules by their common names, e.g., thyroxine or its even simpler name, T4. I will also refer to L-tyrosine as tyrosine.

Evidence-based medicine and thyroid disease treatment policy

There has been an increasing impetus in recent years for physicians to draw, as much as possible, on the entire body of knowledge relevant to their profession when making treatment decisions rather than only on their personal experience. Sackett et al. (1996) describe it as the "conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients" and describes it as "integrating individual clinical expertise with the best available external clinical evidence from systematic research." They are also careful to point out that, in the absence of an applicable "randomised trial," that a physician should seek out "the next best external evidence and work from there." Most fundamentally they say, "Good doctors use both individual clinical expertise and the best available external evidence." 

What are the criteria for deciding the best treatment decision? Some mentioned in the literature are longevity, quality-adjusted life years, occurrence of or time to an event such as a heart attack, and of course the surrogate variables, i.e., risk factors, for the diseases that claim the most lives.  Quality-adjusted life years (QALYs) are a combined measure of longevity and the quality-of-life factors 1) degree of mobility, 2) pain/discomfort level, 3) ability to perform self-care, 4) level of anxiety or depression, and 5) the ability to carry on usual activities (Phillips, 2009).  Sometimes the decision involves difficult trade-offs, which involves consideration of the relative risk of Type I and Type II errors, however.

Livingston and McNutt (2011) point out the pitfalls of applying unvalidated models of ideal medical care to large organization via rigid, oversimplified rules. 

Physicians diagnose thyroid disease largely on the basis of laboratory blood tests, although they are not required by guidelines to screen any groups of patients for thyroid tests; in this way, clinical signs and symptoms play a role in diagnosis by motivating the physician to order such a test. Clinical biochemists perform these tests, which are far from routine, using radioimmunoassay kits, of which many are available on the market; they also determine "reference" ranges for their particular labs using physician input about which patients are disease-free to determine their samples. Scientific teams develop the blood test tools these professionals use. And patients play a role by recognizing their symptoms and signs and calling a physician's attention to them.

Certain policy-making groups play roles of varying influence on standard practice in the medical care industry. The American Association of Clinical Endocrinologists, the American Thyroid Association, the American College of Physicians, the American College of Family Physicians, and the American College of Physicians all recommend screening for hypothyroidism, offering varying guidelines. 

The U.S. Preventive Services Task Force was instituted in 1984 to give regular reports to Congress regarding their findings regarding "evidence-based" recommendations about which screening (of conditions in asymptomatic patients) preventive care services are recommended, based on the "balance of their benefits and harms" (USPSTF, 2014); these evaluations are given without regard to financial considerations.  Although the USPSTF was originally intended to be an advisory group grading the quality of clinical research supporting a wide variety of medical services, the Patient Affordable Care Act (Office of the Legislative Counsel for the Use of the U.S. House of Representatives, 2010) now ties its grades to insurance coverage.   This is cause for concern because of the differing goals of the USPSTF and the ACA, especially in regard to fields that have been sparsely covered by clinical trials and because of their discrepant weighting of financial considerations; procedures which the USPSTF has flagged as needing further study run the risk of not being covered by ACA insurance plans even though they have been part of standard medical practice for a long time, are safe and affordable and had once been awarded "Generally Regarded as Safe" (GRAS) status.

Some of these concerns have been addressed by NIH researchers Villani et al. (2008), who broke down by funding source categories (government, industry, nonprofit or university, and "unknown") and disease categories the number of studies that USPSTF considered in making its recommendations.  There were 17 studies of "thyroid dysfunction," 41% of which were financed by the government, 6% by industry, 12% by nonprofit or university, and 47% by unknown sources.  Thyroid disease might cause problems in the category of "cognitive impairment in older adults," which involved 255 studies, 55% of which were financed by the government, 29% by industry, 33% by nonprofit or university, and 12% by unknown sources.

Thyroid structure and function basics

The hypothalamus-pituitary-thyroid "axis" (where the thyroid gets its orders) and its partnership with its growth hormone counterpart

The hypothalamus, the pituitary gland and the thyroid gland are united in a negative feedback system called the HPT axis.The hypothalamus, a part of the brain, controls energy balance (Bolborea and Dale, 2013); its paraventricular nucleus (PVN) contains neurons secreting thyrotropin releasing hormone (TRH), which stimulates the anterior pituitary gland, which in turn stimulates the thyroid gland to increase its output via the hormone thyrotropin, more familiarly known as thyroid-stimulating hormone (TSH), which in turns causes the thyroid gland to produce the hormones triiodothyronine (T3) and thyroxine (T4); Rising levels of these two thyroid hormones cause the hypothalamus to reduce its TRH output. To add to the confusion, Varghese et al. (2008) report that their research indicates that the intestines can also produce TSH when stimulated by a viral infection.

TSH stimulation causes mitosis (cell division) in the thyroid, the amount increasing as TSH increases (Ealey et al. 1985); there are other, lesser, stimulants of thyrocyte proliferation, such as estradiol (Gabriela et al. (2012)), some antibodies to the TSH receptor (Morshed SA, 2013) and, if taken internally, lithium (Rao et al., 2005).  The thyroid would atrophy without TSH under normal conditions, so there is a certain ideal level that maintains the thyroid at a constant desirable mass; if the TSH is too high and growth exceeds apoptosis (programmed or "normal" cell death), the number of cells increases and a goiter develops; on the other hand, if TSH is reduced, provided adequate iodine is available, apoptosis increases and involution (the opposite of growth) reduces the thyroid's size.  This provides a plausible explanation of why individuals with some degree of thyroid failure can have normal T4 and T3 values:  when TSH stimulation causes an increase in the number of thyroid cells, this compensates for underperformance on the part of the individual cells. This is a possible explanation for subclinical hypothyroidism.

Sometimes, however, environmental stresses, such as Vitamin E deficiency and both iodine deficiency and excess, can lead to thyrocyte necrosis, i.e., abnormal cell death, caused by injury; necrotic cells tend to swell rather than to shrink, as apoptic cells do, maintaining some of the thyroid enlargement caused by a goiter (Mutaku et al. 2002).   Because necrosis causes enlargement rather than shrinking, it may contribute to a goiter's permanence. 

TSH works with insulin-like growth factor 1 (IGF-1) and insulin to stimulate DNA synthesis in thyroid cells (Brenner-Gati et al., 1988). IGF-1, in turn, is produced in the liver in response to stimulation by growth hormone (GH), which is produced by the anterior pituitary gland to perform one of the main functions of inflammation, i.e., to stimulate rebuilding of damaged tissue, its production in turn stimulated by hypothalamus-produced growth hormone releasing hormone (GHRH)

This process may be impeded by the anti-inflammatory action of cortisol, which is produced by the adrenal cortex in response to stress, which (as is discussed later) prevents the natural night-time rise in TSH if given in high enough doses.

The hypothalamus acts as a switchboard in this system, putting out hormones in response to other hormones sent from fat cells and digestive system organs. Some stimulate the appetite via the arctuate nucleus; others influence the feedback system that involves the thyroid gland and its hormones by stimulating the paraventricular nucleus (PVN). Endocrine hormones travel through the blood to reach their destinations. Recent research is giving us information about special cells in the hypothalamus, tanycytes, which might be the communication bridge between the central nervous system and the endocrine system.

Figure 1. This gives an idea of the components of the feedback system involving the thyroid, but not the suppressive actions; not represented are the feedback mechanisms of the thyroid hormones on the pituitary gland and on the hypothalamus. Only three hypothalamus nuclei are represented: the paraventricular nucleus (PVN), the ventromedial nucleus, and the lateral hypothalamus. The hormones involved in the appetite regulation part are described by Saladin (2007, 1002-4).

This is a negative feedback system. The hypothalamus, the pituitary gland and the thyroid are referred to as the HPT axis. The hypothalamus performs its regulatory function by sensing T3 and T4 levels and raising or lowering Thyrotropin Releasing Hormone (TRH) accordingly. This diagram shows its interaction with another system regulating appetite and with another regulating glucocorticoid levels (of which cortisol is one, which in turn lower TRH levels as they rise. In response to cortisol stimulation, the liver produces glucose from the glycogen it stores and sends it and free fatty acids into the blood.

The thyroid and its hormones

The thyroid is an endocrine gland which, in partnership with many other parts of the body, determines the pace of metabolism in the body. The thyroid produces two hormones, T3 (in small amounts) and T4 (in large amounts). This production activity takes place inside follicles within the thyroid gland. T3 is the metabolically active hormone, producing a short-lasting effect; it is also produced from T4 by the removal of a particular iodine atom by special enzymes located in various organs and tissues.

When they enter other body cells, such as those of the liver, thyroid hormones act in the mitochrondria, energy-producing units found in the nucleus. They have two major functions here, increasing the rate of production of 1) heat, directly via a process called "proton leak" (the only thing affected in hypothyroidism, in which it is reduced) and 2) potential chemical energy in the form of adenosine triphosphate (ATP) via "oxidative phosphorylation" (affected in both hypothyroidism and hyperthyroidism, reduced in the former and increased in the latter) (Harper and Brand, 1993).

The thyroid's basic unit: the follicle

The basic unit of thyroid tissue is the follicle, a spherical object containing a colloid-filled lumen enclosed in a one-thyrocyte-thick layer; the small spaces between follicles contain capillaries and small lymphatic vessels passing among the follicles.  The thyrocytes are epithelial cells that interface with the blood through their basolateral (outer) surface and with the lumen (inner space) via their apical (inner) surface.  Thyrocytes produce the glycoprotein thyroid hormone precursor thyroglobulin (Tg, a target of one type of antibodies, known as Tg-Ab, which mark Tg for destruction) from tyrosine (a mostly nonpolar amino acid which enters the thyrocyte through passive transport), and secrete that and iodide ions that they receive from the blood into the colloid (Marino and McCluskey, 2000).  An important enzyme, thyroperoxidase (TPO, another target of some types of antibodies, known as TPO-Ab) has been found on both the apical and, less frequently, on the basolateral surfaces of thyrocytes (Zimmer et al, 1997).  TPO works there with hydrogen peroxide (H2O2) to complete the building of T3 and T4 by reshaping and cleaving thyroglobulin and bonding it with iodide ions; these hormone precursors are returned from the colloid to the thyrocyte for minor modifications before being sent into the blood as completely formed T3 and T4. The antioxidant Vitamin E is needed to clean up excess H2O2 created for this hormone-building process; the higher TSH levels are, the more Vitamin E is needed, as Mutaku et al. (2002) conclude.

Thyroglobulin is a very large protein, with a molecular weight of about 660,000 grams per mole (Food and Nutrition Board, Institute of Medicine, 2001); it consists of a peptide backbone with 123 tyrosine molecules branching from that backbone. Tyrosine, as discussed above, is an amino acid consisting largely of one phenyl group (a 6-carbon ring) two bonded. T4 and T3 are very small molecules, which are each constructed from two tyrosine molecules taken from a thyroglobulin molecule by the enzymatic action mentioned above in the colloid; they initially remain attached to the thyroglobulin peptide backbone and enter the thyrocyte via endocytosis on its apical side, where they break away and leave the thyrocyte via its basolateral surface and enter the blood, since they are fat-soluble, through passive transport (Saladin, 2004). 

Both deficient and excessive iodide levels relative to existing thyroglobulin can produce a goiter; excessive iodine levels can lead to the formation of goiters because of interference (congestion) created by too many iodide ions according to the Food and Nutrition Board, Institute of Medicine (2001).  Is it possible that the goiter is created in the case of excess iodine ions instead by the HPT axis increasing thyroid hormone production to keep the iodine ions in the thyroid from increasing in number and therefore creating a chemical as well as physical problem?  An important implication here: the presence of a goiter in an individual is not enough to determine whether iodine excess or deficiency is present, although population studies can give helpful clues about iodine in the local environment.

TSH increases the rate of passage of iodide ions into the thyrocyte by stimulating the increase in the number of its sodium/iodide symporters (NIS) integral proteins in thyrocyte cell membranes, but it needs the presence of IGF-1 to do this (Ock et al., 2013). These mediate the transport of iodide ions from the blood into the thyrocyte via the basolateral cell membrane, maintaining the concentration of iodide ions inside the thyrocyte vs. those outside it, in the blood, at a ratio of 20-40 to1. What I'm not clear on is whether increasing TSH increases the number of NIS in the cell membrane of individual thyrocytes or whether the increase in thyrocytes accounts for the increase in the total number of NIS. An NIS can be carried to and from the cell membrane within the cell in vesicles, with TSH drawing them into that cell membrane, thereby creating more opportunities for iodine ions to enter the thyrocyte. Finally, when iodide ion concentrations rise to a certain threshold level, TPO ceases its binding of these ions in organic molecules such as hormones until the iodide ion concentration drops below that level; this phenomenon, known as the acute Wolff-Chaikoff effect, lasts up to 50 hours after a single (over)dose but this implies that continually excessive iodine intake could result in long-term hypothyroidism (Dohán et al., 2003)However, up to this threshold value, it stands to reason that thyroid mitosis and the production of thyroid hormones will increase as iodide ion input increases according to the system this review describes.

NIS also found in the breast, salivary glands, choriod plexus (tissue which lines the brain's ventricles and produces cerebrospinal fluid) and gastric mucosa, with the lactating breast getting the lion's share of the non-thyroid iodide ions (Institute of Medicine, Food and Nutrition Board, 2001); Tazebay (2000) observed the same about the cancerous breast.  Dohán et al., 2003 point out that the lactating breast has a local NIS to provide iodide ions to the nursing newborn; this would tend to lower available iodide ion levels in pregnant and nursing women. Estradiol, the predominant estrogen in women during their reproductive years, has been shown to inhibit this process by down-regulating the thyrocyte symporter gene (Furlanetto et al., 1999).

Although these symporters are the only means by which iodine enters the thyrocytes, they also allow in other ions with a -1 charge, although the "pull" it exerts on these ions varies greatly. Cl-chlorate (ClO3-) and thiocyanate (SCN-) ions are the most competitive inhibitors, practically, in fact, as competitive as iodide ions, while perchlorate ions (ClO4-) are apparently "blockers," though I do not understand what that implies in terms of chemical reactions. Bromide ions, on the other hand, are "pulled" in by only about a quarter of the force that iodides are, and bromate ions only about half of that (Dohan et al, 2003). Thiocyanate ions are found in cruciferous vegetables, e.g., broccoli and cabbage, but the amount in normal consumption of these vegetables is not considered to be a problem in those getting enough dietary iodine and selenium and not possessing certain rare genetic defects.  Cooking these vegetables helps to mitigate this problem.

It is possible that as breast tissue evolved to handle substantial amounts of iodide ions in order to transfer it to nursing infants, this tissue came to depend on the presence of this form of iodine to function normally on a cellular level.

Pendrin, the sodium-independent chloride/iodide transporter is an integral protein that transports iodine from a thyrocyte to the colloid through the apical cell membrane separating them.

The detected presence of antithyroid antibodies is considered to be the hallmark of Hashimoto's thyroiditis (Amino et al., 2002), regarded as an autoimmune disease and is currently accepted as the cause of nearly all hypothyroidism in the U.S. (Merck, 2006).  What causes antithyroid antibodies to form?  Could it be that they are triggered when excessive iodine causes an upswing in T4 and T3 production? Perhaps to protect itself, the body may launch an autoimmune attack on the thyroid to limit its activity.  The findings of Dr. Hashimoto in his native iodine-rich Japan in the early twentieth century suggested this, although the issue seems to be up in the air; more discussion on this topic is found below.

Figure 2. The main functions of the thyroid follicle, with one thyrocyte blown up and the activities in the colloid shown on the left. Three forms of molecular transport into and out of the thyrocyte are shown: passive transport (tyrosine, T3 and T4), active transport (Na+ and I-, via pendrin) and endocytosis/exocytosis (thyroglobulin, i.e., "Tg"). "ER" stands for "endoplasmic reticulum."

Other body systems processing thyroid hormones

Thyroid-binding globulin (TBG), transthyretin and albumin, all produced by the liver, together bind most T4 (99.97%) and T3 (99.7%) (Mebis and van der Berghe, 2009) so that they cannot react and transport these hormones in the blood; the unbound portion is known as free T3 (FT3) and free T4 (FT4).  T3 and T4 need transport proteins to travel through the blood rather than being randomly tossed around because T3 and T4 are mostly hydrophobic and need a force to attach them to the blood water molecules. The transport proteins link to these hormones at their hydrophilic/nonpolar ends and link to water molecules with their polar/hydrophobic ends.

In the healthy individual, TSH and FT3 levels follow a similar circadian rhythm, with FT3 slightly delayed (Russell et al., 2008).  Since FT3 is the actual amount of chemically active hormone available to the body, it is in theory the one most closely linked to clinical manifestations of hypothyroidism; however, but it's not clear to me that TSH follows that pattern in a person with thyroid disease and therefore may not accurately reflect the severity of signs and symptoms. 

There are three different iodothyronine deiodinase enzymes (D1, D2, D3) which process T4 and, in one case, T3; as their collective name implies, their role is remove an iodine atom (turning it into an iodide ion) from one of these molecules, sometimes making the latter chemically active, sometimes the opposite, depending on the location of that iodine in that thyroid hormone.  Each of these enzymes is determined by a single gene. D1, which operates mainly in the liver, kidney, anterior pituitary and thyroid; converts T4 to T3 by removing the iodide ion (which is recycled) from T4's outer ring.  D2, found in the brain, skeletal muscle and anterior pituitary, does the same things as D1, only locally, and seems to be activated in hypothyroidism (Mebis and van der Berghe, 2009).  D3, on the other hand, is present and only locally operative in such rapidly growing tissue as the skin, placenta, fetal tissue and intestines and in the brain, especially the hippocampus and the temporal cortex (Santini et al., 2001); it has also been found in malignant tumors which apparently "express" D3. It removes an iodide ion from the center ring of tyrosine in T4, generating reverse T3 (RT3)(Mebis and van den Berghe, 2009); by a similar process it also creates diiodothyronine (T2) from T3 (Bolborea et al., 2012).  D3 is also found in the brain, with especially high levels found in the hippocampus and temporal cortex and lower levels found in the thalamus, hypothalamus, midbrain cerebellum, the frontal and parietal cortices and the brainstem (Santini et al., 2001).  The D1 enzyme contains selenium; however, evidence suggests that this mineral is not found in D2 (Chanoine et al., 2001).

By producing RT3 and T2 instead of T4 and T3, D3 effectively has the opposite effect of D1 and D2: RT3 and T2 have very little of the effect that T3 and T4 have on tissue cells, but they do suppress TSH (to a significant but lesser degree), which in turn lowers T3 and T4 production in the thyroid.

In vitro cell research suggests that tanycytes are instrumental in maintaining the HPT axis negative feedback system by secreting a chemical that "degrades" TRH when they sense the presence of T3 at their locations in the hypothalamus. They also apparently produce enzymes D2 and D3, downregulating the former and upregulating the latter as hours of daylight decrease, which in turn lowers T3 levels (Bolborea et al., 2012).

The endocrine system works closely with the nervous system and immune system. There are two basic TSH "signals," i.e., repetitive wave patterns, contributing to form the shape of the amplitude curve of TSH hormone levels over time: the cyclical sine-wave-shaped one that repeats every 24 hours, and the pulsatile, which spikes about 17 times every 24 hours in healthy individuals (Roelfsema et al. (2009). In order to separate these two "signals" in TSH data, these researchers used a computer algorithm called deconvolution.

Some individuals have special difficulty converting T4 to T3 because a genetic defect causes an enzyme's action to block the activation of D2 (mice study, Werneck de Castro et al., 2015).  U.K. researchers Panicker et al. (2009) discovered that subjects with a less common (16% of the study population) homozygous D2 gene variant did more poorly on the General Health Questionnaire 12, a WHO-derived document. McAninch et al. (2015) followed up on this finding by concluding that this defect affects cellular biochemical activities that are associated with nervous system functions, abnormalities of which have been shown to cause "neurodegenerative disorders such as Huntington's disease."  It was not clear from the abstract of the McAninch article whether this problem was associated with Alzheimer's dementia; perhaps the full version of this article provided this information.

The parafollicular cells

These cells are found in the connective tissue among the thyroid follicles and produce calcitonin, which blocks the action of osteoclasts, which remove calcium from bones. They express TRH, thereby having some influence on thyroid function.

Relationship to the nervous system, the immune system and to other endocrine glands

The Merck Manual (2006, p. 1194) refers to "drugs such as dopamine and corticosteroids, which decrease pituitary secretion of TSH, resulting in low serum TSH levels and subsequent decreased T4 secretion" in connection with diagnosis of euthyroid sick syndrome (abnormally low T3 and T4 levels in a patient without thyroid disease but with a disease affecting another part of the body).  Abbott Labs (2013) says that the use of "Dopamine/Dopamine Agonists" and "Glucocorticoids" may "result in a transient reduction in TSH secretion" when administered at high enough doses; this makes sense because the lowered TSH would trigger a TRH increase from the hypothalamus, stimulating the pituitary to increase its output of TSH.  One has to ask, though, what is the effect of habitual or long-term use of these substances?  Suppose a patient has a condition which keeps the levels of at least one of these substances constantly high?  Besides, if TSH is pulled down into the normal range by dopamine intake or stimulation, could a diagnosis of hypothyroidism be missed?

In a nutshell, the versatile nonessential amino acid tyrosine is a building block of both the catecholamines (the neurotransmitters dopamine, epinephrine and norepinephrine) and of T3 and T4. 


It has long been known that hypothyroidism has been linked to high dopamine levels.  Dopamine is a catecholamine, a neurotransmitter which activates the sympathetic nervous system.   Besses et al. (1975) concluded that a dopamine infusion "inhibited" TSH and prolactin. Scanlon et al. (1979) discovered that a dopamine-blocking agent raised daytime TSH in subjects, more so in women than in men.  Crocker et al. (1986) showed that hypothyroidism in rats (induced experimentally by exposure to radioactive iodine) increased dopamine receptor concentrations in the ventral striatum (which houses the nucleus accumbens, now believed to be the brain's pleasure center.)  It is now generally accepted that dopamine suppresses the HPT axis altogether (Haugen, 2009).

DeZegher et al. (1995) raised the concern that dopamine infusion therapy, commonly applied to infants with heart problems to help their heart contractions, could mask the presence of hypothyroidism in those patients and illustrated this by inducing a dramatic rise in TSH in infants receiving a dopamine infusion by cutting off that infusion.  Diarra et al. (1989) examined tyrosine metabolism in several types of rat tissue and concluded that catecholamine synthesis was increased in the medullas of the adrenal glands (epinephrine and norepinephrine) and the brainstem, i.e., the part of the brain adjoining the spine, in hypothyroid patients.

Caffeine indirectly causes dopamine levels to rise. Benvenga et al. (2008) showed that when human subjects drank coffee and took T4 tablets together, their T4 blood levels were lower and peaked later than those of controls; however, in the in vitro stool studies, coffee was determined to be a weaker sequestrant than dietary fibers, aluminum hydroxide, and sucralfate, an anti-ulcer drug.

What's also interesting is that exercise raises brain dopamine levels (Sutoo and Akiyama, 2003). Exercise, in fact, tends to raise overall TSH levels anyway (citation in a later section).

Smoking, which involves the intake of the dopamine agonist nicotine, has been recognized to be a confounding factor in studies comparing patients on the basis of TSH levels, as is discussed later. According to Norwegian researchers Jorde and Sundsfjord (2006), smokers had statistically significantly lower TSH levels and higher T3 and T4 levels than non-smokers; because of the nature of HPT axis feedback systems, this suggests that smoking raises T3 and T4 levels, which in turn suppress TSH levels.

L-DOPA is converted to dopamine in the basal ganglia and substantia nigra (in the brain), involving an enzyme called L-DOPA decarboxylaseL-DOPA in turn is created from the amino acid tyrosine via the catalyst tyrosine hydroxylase, which is found in the central nervous system, peripheral sympathetic system neurons and adrenal medulla. L-DOPA also stimulates the release of GHRH from the hypothalamus (Chihara et al., 1986). Could this explain why a rise in dopamine lowers TSH levels? Maybe the introduction of dopamine lowers L-DOPA levels because less of it is needed to create dopamine. This in turns lowers IGF-1 levels, which in turn lowers the maximum level of TSH that can be used. This in itself could induce hypothyroidism, but what lowers TSH? Perhaps the HPT axis responds to this situation by producing less TSH so that as little as possible is wasted.

Tyrosine is also a precursor of thyroglobulin, in turn a precursor of the thyroid hormones.  This suggests that some metabolic pathways leading to the production of dopamine and the thyroid hormones compete for tyrosine.


Cleare et al. (1995) concluded that hypothyroidism is associated with reduced "central" serotoninergic activity and with clinical depression (determined by responses to two depression rating scales).  Cortisol and prolactin levels were lower among hypothyroid subjects than in controls. Unfortunately, today the medical establishment appears to view low serotonin levels as diagnostic of depression, to be treated by Selective Serotonin Reuptake Inhibitors (SSRIs).


Patients with Cushing's syndrome, a condition in which the adrenal cortex hormone cortisol is excessively high, have lower TSH levels than healthy subjects, especially during the evening and night, when only the latter experience a substantial rise in TSH (from an average of about 1.0 to 2.0 mIU/L) that starts at about 8 pm, peaking at around 11 pm.  This is explained by less vigorous pituitary pulses, i.e., smaller in amplitude and mass, according to Roelfsema et al. (2009).  The ultimate cause of TSH suppression associated with cortisol use appears to be TRH suppression in the hypothalamus (Alkemade et al., 2005, Haugen, 2009). This suggests that high cortisol levels might mask thyroid failure by lowering TSH levels into the normal range in those whose hypothyroidism might have been flagged otherwise. 

More recently discovered, neuropeptide hormones include Neuropeptide Y, expressed in the PVN of the hypothalamus (Pert, 2004).  It apparently causes release of corticotropin-releasing hormone (CRH), which in turn stimulates the anterior pituitary gland to produce adrenocorticotropic hormone (ACTH), which stimulates the adrenal cortex to produce cortisol.

Can high levels of emotional stress misleadingly lower the TSH in patients whose hypothyroidism would be discovered otherwise through TSH blood levels?  And does the adrenal cortex pinch-hit for for a failing thyroid?  There are a lot of troubling questions here.

The immune system

Autoimmune disease, in the form of Hashimoto's thyroiditis, is considered to be the major cause of hypothyroidism in American today.

Cytokines, e.g., tumor necrosis factors, interleukins and interferons, are messenger molecules that allow the immune and endocrine systems to communicate, and play a complex role in regulating the deiodinases, according to rat studies.  They have been shown to stimulate D1 (in the short-term, with levels dropping after the first hour, but still always higher than in the controls) and D2 levels (rising through at least the first 24 hours, and higher than the controls after four hours) in the rat anterior pituitary, while lowering liver (always lower than controls but basically steady) and blood D1 blood levels (dropping below controls within four hours and but rising almost to that of the controls in 24 hours);  It isn't clear why this happens; the resulting rise in T3 levels in the pituitary should cause the latter to lower its TSH output, and it appears that it does so briefly (not surprising, since T3 has a brief effect), especially four hours after the cytokine-stimulating infusion.  This also drives down blood TSH levels, but in a nonlinear way: they are lowest at four hours after a lipopolysaccharide (LPS) infusion, experimentally introduced in order to stimulate the production of cytokines, but after a high point at one hour after that infusion, they drop to almost the same levels as the controls at 24 hours after the LPS infusion (Baur et al., 2000).

Disruption of the circadian cycle, i.e., by varying the timing of daily light and dark exposure, can intensify immune cell response (by not increase the number of immune cells) by elevating the blood levels of interleukin 6 (IL-6), a cytokine, triggered by an LPS infusion. 

History: from iodine nutrition management to thyroid hormone replacement

Although iodine deficiency (and, less often, excess) has considerable medical importance, it has been treated almost exclusively as a public health issue, rather than a medical one, by the countries of the industrialized world, although its consequences in terms of thyroid disease are generally treated with hormone replacement rather than be repairing a nutritional deficiency when the latter is diagnosed.  Salt iodization has been the public health strategy adopted by 70 countries, but this has proved difficult because of wide regional variations in environmental iodine.   Although iodization of salt processed "for human and animal consumption" has been pushed in Europe since the 1980s, less than 50% of European households use iodized salt, in contrast with 90% in North and South American counterparts (NIH, 2011), although the use of iodized oil has also been effective in iodine-poor regions in Europe. Andersson et al. (2007) claim that ongoing monitoring is necessary because compliance with salt iodization policies has a tendency to fall off, which suggests to me that discrepancies in reported iodized salt consumption among different countries may be due to variations in monitoring.  Median urine iodine levels range from 115 mcg/L in central Switzerland to 728 mcg/L in coastal Hokkaido, Japan (Zimmerman, 2005). 

It's now understood that those living close to oceans are less susceptible to iodine deficiency than those living inland, especially those living in mountainous areas, since iodide ions are transported by air currents from the ocean inland, where they are absorbed by the soil and are washed down the mountains by rain. Adhvaryu et al (2013) showed that there were even more striking differences between goiter rates in the northern states and the southern ones in the United States in 1917 WWI draft data, and that after about 30 years of salt iodization there were still some areas with high rates of goiters, though only in the extreme north of the country. These researchers theorized that this north-south divide was caused by a glacier during the Ice Age.

However, distributing iodine in salt in ways that reflect those geographical differences has not been practical.  Coping with wide variations in individual dietary iodine needs makes this even more difficult, since pregnant women in particular have higher needs and more than half (56.9%) of pregnant American women "surveyed during 2005-2008" had subnormal iodine blood levels (<150 mcg/L), with the corresponding median only 125 mcg/L (Caldwell et al., 2011).

Goiter, myxedema, cretinism, iodine and understanding of how the thyroid gland works: the early European contribution

Understanding that the thyroid gland had a purpose, that it produced a molecule that the body needed to prevent hypothyroidism syndromes called myxedema and cretinism and that iodine, necessarily obtained through the diet, was necessary to build this molecule, was mostly the work of Swiss, French and German scientists during the 1800s, although resistance from their conservative societies kept iodine from being used therapeutically to treat these diseases on a large scale, according to Carpenter (2005). The Swiss physician J.F. Coindet proposed treating goiter in individuals with iodine administered by and monitored by physicians in an 1820 paper; this was perhaps the only time this option was considered.  He actually treated patients with it, with iodine (the implication from Carpenter being that it was isolated from seaweed) dissolved in distilled alcohol, amounting to a daily dose of 165 mg; he reported no toxic effects, although some influential individuals claimed that their experience was otherwise.

An early clinical trial testing iodine, in the form of potassium iodide pills, as a treatment for goiter, took place in France in 1873, using a daily iodine dose of 7.6 mg for 75 days or until the goiter went away. It apparently was successful, with 74% of the subjects being cured; no adverse events were reported (Carpenter, 2005).

Contributions from the United States and Japan: from salt iodization to T4 replacement

Iodine deficiency and its treatment with salt iodization

Sometimes dramatic improvements in public health require the action of a "hero," a well-credentialed person with an important insight, progressive vision on how to act on it, and who is socially and/or professionally prominent. Such a person was American scientist David Marine, who organized, got acceptance and support for, and performed the first clinical trial (1917-1922) using iodine as the intervention that resulted in a change in official policy.  Having observed many dogs with goiters in Cleveland, Marine experimentally reduced goiters in these animals and suspected that there was a regional iodine deficiency problem that affected humans, too.  Although he was employed as a physician at Johns Hopkins University's medical school in Baltimore, Maryland at the time, he decided to return to the Goiter Belt part of the United States to perform an iodine supplementation clinical trial on schoolgirls in Akron, Ohio when permission to conduct it was denied in Cleveland on the grounds that iodine was dangerous. The trial was a success, proving both safety and efficacy.

Meanwhile, Love and Davenport (1920) estimated the goiter rate by state and discovered dramatic differences: these rates per 1000 ranged from 26.91 in Idaho to 0.25 in Florida (Table 18 in their article). Universal salt iodization, in spite of the regional differences shown in the Love and Davenport study, became an official means in the U.S. in 1924 to the end of eliminating goiters. The Morton Salt Company in the U.S. began to add potassium iodide (KI) particles to its salt and the rate of goiters in the Great Lakes area soon dropped to a small fraction of what its original level.  Unfortunately, there was a surge of thyrotoxicosis cases, resulting in an apparent excess of 102 "deaths in Detroit from goiter" in 1926 although this problem "died away after about 2 years," according to Carpenter (2005), who pointed out that similar problems were reported in Tasmania, Europe, South America and central Africa, and that "it now seems agreed that the problem occurs typically in people whose goiter, over long years of relative iodine deficiency, has become nodular and that this tissue is 'out of control' so that as more iodine becomes available to it the output of hormone(s) climbs to toxic levels" (p. 679).

Salt iodization has always been a voluntary program in the U.S.; processed food typically contains uniodized salt and must by law indicate in its labeling when it does contain added iodine (NIH, 2011).

Apparently, putting iodine in public water supplies was briefly considered. Olesen (1927) was skeptical of delivering iodine either in this form or via salt, implying that it was dangerous to administer iodine to those without goiters.  WHO (2008) explained that maintaining consistent levels of iodine in public water supplies would have been more difficult than doing so with salt, since 1) a major monitoring effort would be needed to cover the great number of different water sources (presumably municipalities) involved and 2) iodine is "unstable" in water (unlike fluoride ions?) On the other hand, because different parts of the country contain greatly varying environmental iodine levels, iodized public water would seem to worth considering for tailoring dietary iodine to local conditions.

However, the pendulum then swung the other way, with iodine excess in the U.S. gaining recognition as being much more common than iodine deficiency.  Since Japan had long been noted for its high iodine intake via dietary seaweed, American policy makers apparently connected the dots and decided that excessive iodine intake was the problem.  The FDA banned the use of iodine as a disinfectant in dairy cows in response to a flurry of studies coming out between 1978 and 1986 and as a dough conditioner in the bread-making industry, and American iodine intake, as measured by urinary iodine, dropped precipitously. 

However, this drop-off in iodine intake continued long after these measures had been instituted, and the CDC expressed concern in the National Health and Nutrition Examination Survey (NHANES) III study (Hollowell et al., 1998) that iodine deficiency was threatening to return and recommended follow-up, pointing out that median U.S. urine iodine levels had dropped from about 320 mcg/L over 1971-74 to about 145 mcg/L over 1988-1994; the percentage of the U.S. population having inadequate iodine levels, i.e., less than 100 mcg/L, according to World Health Organization (WHO) standards, increased from about 7% to about 32% in this same time interval (Fig. 1, p. 3405); both numbers were considered acceptable according to the WHO's standards, i.e., no more than 50% below 100 mcg/L.  These researchers recommended continuing follow-up of iodine levels in both NHANES IV and in the FDA's Total Diet Study and added, "Surveillance of thyroid diseases should be emphasized, but we should not wait for the prevalence of goiter to increase or for changes in thyroid disease patterns to occur due to decreased iodine intake (my italics)." (p. 3408) Later on, the CDC (Blount et al., 2006) determined that the geometric mean of urine iodine in the U.S. was 126 mcg/L for women and girls at least 12 years old. In a later CDC study (Caldwell, 2011), median U.S. urine iodine concentrations were 164 mcg/L for both 2005-2006 and 2007-2008, with 9.8% and 8.8%, respectively for those time periods, having such concentrations below 50 mcg/L.  Pregnant women surveyed over the entire period had a median iodine concentration of 125 mcg/L.   NOTE: these numbers were reported in "mg/L" in this abstract, which I assumed to be a mistake. Lee (2014) covered this ground also, expressing concern about the apparent decrease of iodine intake and the lack of recent monitoring in the US.

Oddly, de Benoist et al. (2004), a European group working for the WHO, reported that Americans were getting too much iodine, with a urine iodine median somewhere between 200-299 mcg/L. However, they also reported that goiter prevalence in the Americas was only 4.6%, the smallest of any geographical region in their survey; they drew their information from undisclosed sources in the WHO Global Database on Iodine Deficiency, which in turns obtains its information from surveys of publications in databases such as MEDLINE. Troublingly absent from the study are Japanese and South Korean data.  However, Zimmerman et al (2005) filled this gap by determining the median urine iodine concentration in coastal Hokkaido in Japan to be 728 mcg/L in a paper concluding that an iodine intake leading to less 500 mcg/L in urine iodine was safe for children aged 6-12 years. Chow et al. (1991) had already observed that an estimated total daily dose of 750 mcg (involving an administered 500 mcg dose) slightly lowered free T4 and slightly raised TSH in Welsh adults, with none in the sample developing "biochemical hypothyroidism," with these numbers appearing to reach steady state by about 28 days.

Adding to the complexity, the American Medical Association was promoting the revocation of salt's Generally Accepted as Safe (GRAS) status and the Center for Science in the Public Interest has filed a petition to that effect so that the FDA can regulate the amount of salt in food for sale (AMA, 2008).  The FDA has examined iodine status in the U.S. population in the Total Diet Study since 1961 (Murray et al., 2008).

The shift to T4 replacement therapy

Sawin (2002) provides an account of the sea changes in the therapeutic approach to hypothyroidism. Until the 1950s, American physicians had treated goiters mainly with surgery. But three significant developments during that decade radically changed their role in the treatment of thyroid disease: 1) A Japanese physician's 1912 paper describing an apparent autoimmune thyroid condition, 2) the synthesis of T4 and its marketing as Synthroid, and 3) the invention of the radioimmunoassay (RIA), an analytical method capable of measuring very small blood concentrations of molecules such as hormones. Today, hypothyroidism is assumed to have autoimmune origins, i.e., to originate in Hashimoto's thyroiditis, unless pituitary involvement is suspected (Merck, 2006, p. 1194).

"Screening for Thyroid Disease" by the U.S. Preventive Services Task Force (2004) is undecided about whether to recommends routine screening for thyroid disease by testing TSH levels, arguing that clinical signs or symptoms should be present before any diagnostic or treatment steps be taken.  The main problem is the great downside of overdiagnosing hyperthyroidism, possibly leading to unnecessary destruction of thyroid tissue and exposure to radiation.  However, this group is currently trying to arrive at a recommendation.

Broda Barnes, a hypothyroidism researcher before his time?

Barnes received his M.D. in 1937, when a complicated process of measuring basal metabolism was the diagnostic standard for thyroid disease and before the radioimmunoassay was developed. He began his thyroid research in 1930 as an undergraduate, having been assigned to this topic as a physiology dissertation subject by his advisor at the University of Chicago.  He found in his studies that rabbits whose thyroid glands had been removed were afflicted with many infections and a great variety of other physical problems and died at less than half their normal life span.  As a medical student afterwards at Rush Medical Center, he saw in some of his patients signs that reminded him of the problems affecting the rabbits he had studied. Although apparently crude methods existed for measuring T3 and T4 levels, he considered them to be unfeasible.  Instead, he discovered that oral body temperature, taken first thing in the morning, was a better indicator than the currently used measurement of basal metabolism rate, and published his findings in 1942 (Barnes and Galton, 1976, p. 43.)  He later modified this approach by using the armpit temperature, determining the normal range for this temperature to be 97.8-98.2 degrees Fahrenheit for all adults (p. 46).  Unfortunately, although his approach was initially ground-breaking, he apparently continued to use it through 1976, the publication date of this book, which contains no mention of TSH assays as diagnostic tools.  To be entirely fair, however, the precision of TSH assays at that time was awaiting great improvement. Another problem was that Barnes did not use the metric system, vital to the small units necessary to work with hormones (although he might not have been working with pills but with animal thyroids).  He prescribed doses in grains, e.g., "two grains of thyroid" in 1967 (p. 150). 

However, Barnes' diagnostic method has been set aside, not simply because of the increasing improvement of the quality of the TSH assay but because of the apparent widening of the normal range for body temperature; it is generally accepted in the USA today that a temperature below 95(in effect, 95.0) F constitutes a medical emergency and that a temperature above 100.4 F is a fever.  Unfortunately, his studies relating hypothyroidism and susceptibility to infection were not followed up on, perhaps because many of the serious infectious diseases common in the early twentieth century are now preventable and/or curable by vaccines and antimicrobial medications, and some even eradicated or simply confined to what are best described as "invisible" populations.

The Hashimoto Paper

New recognition was given to Dr. Hakaru Hashimoto's 1912 landmark paper (published in a German-language journal, not cited), which established a connection between the known clinical signs and symptoms of hypothyroidism and the histological hallmarks of a new disease, characterized by destruction of thyroid cells by lymphocytes. According to Sawin (2002), The Thyroid, a 1951 textbook by T.H. McGavack, noted that "most cases of spontaneous hypothyroidism have a lymphocytic infiltrate".  By "spontaneous hypothyroidism," they may have meant not related to iodine deficiency.  Several other researchers defined "autoimmune thyroiditis" as a condition involving this infiltrate and not always causing a goiter: in 1956, when urine iodine levels were apparently at their highest, one study induced autoimmune thyroid disease, triggering antibodies against their own thyroglobulin, in rabbits by injecting them with that thyroglobulin, along with Freund's adjuvant to help provoke an immune response, and another detected anti-thyroid antibodies in the blood of patients previously diagnosed with Hashimoto's disease. They found that this "lymphocytic infiltrate" "looked like" that seen in Hashimoto's disease. Although these researchers found it quite difficult to find subjects with "classic" Hashimoto's disease (only 12 in three years). To make a long story short, however, a major paradigm shift took place within 10 years and today Hashimoto's disease is now considered to be the most common cause of hypothyroidism. Yet one question remains unanswered: if it took introduction of a hapten to trigger anti-thyroglobulin antibodies in rabbits, what was causing the problem in humans?

Today, Hashimoto's thyroiditis "is believed to be the most common cause of primary hypothyroidism in North America" and calls for "lifelong" T4 therapy (Merck, 2006).  Today, there is still no consensus regarding the primary cause of this autoimmune condition. Hollowell et al. (1998) suspected that it was caused by temporary iodine excess because Dr. Hashimoto's Japan was noted for its unusually high urine iodine levels, believed to be linked to heavy dietary consumption of seaweed. But other possibilities remain to be explored. As we learn more about the function of the body's natural defenses, we can see how they can attack the thyroid in error, even when other targets, such as invading bacteria or viruses, stimulate their action.  Perhaps childhood illnesses ranging from measles to polio thereby raise the risk of autoimmune thyroid disease later on.

Anti-thyroid antibodies were eventually found in other forms of thyroid disease, such as Graves' disease, a condition that causes hyperthyroidism. 

Although measuring iodine levels and treating iodine deficiency in individual patients seems to be an obvious approach, no measures are being taken to modify treatment with diagnostic urine iodine testing or by the development of iodine pills in the US; autoimmune thyroid disease can be detected with the anti-thyroid perioxidase antibodies (TPO-Ab) test, though this measure is apparently not standard, perhaps because determining antibody presence is not helpful in determining the T4 dose.  

Synthroid and thyroid replacement hormone therapy

Synthroid, a synthetic, bioidentical T4 product, came on the market in 1955 and later came to dominate the market. However, it was not the first synthetic T4 product to be marketed (Hilts, 2001).

The invention of the radioimmunoassay and, later, of the ELISA

The radioimmunoassay (RIA), an analytical method capable of measuring very small blood concentrations of molecules such as hormones was developed in the 1950s, although for decades it was not sensitive enough to measure precisely concentrations near the bottom of the TSH normal range and for a while near its top:  in 1965, it was sensitive only to 5-10 mIU/L, although that sensitivity improved to 0.01 mIU/L by 1989 and to 0.002 mIU/L in recent years, as reported by Arafah (2001). Today, a new non-radioactive assay method, enzyme-linked immunosorbent assay (ELISA), is often used instead.  This precision measurement apparently refers to the consistency in measurements of the same data for a particular assay; however, there may be more variation among average measurements (accuracy) across assays produced by different companies.

Today: What is settled and decided (and what is not) regarding dietary iodine

The World Health Organization (WHO), based in Geneva, Switzerland, has stated that its major concern with respect to the prevention of thyroid disease is that iodine deficiency may cause a reduction in mental function: Andersson et al. (2008, p. vii) emphasize the need to prevent "more subtle degrees of mental impairment associated with iodine deficiency that lead to poor school performance, reduced intellectual ability, and impaired work capacity." With this in mind, the authors of this document did a country-by-country study of iodine levels in the world.

The WHO has set these standards for adult urine iodine levels (in mcg/L): <20: severe iodine deficiency, 20-49: moderate iodine deficiency, 50-99: mild iodine deficiency, 100-199: optimal iodine levels, 200-299: risk of hyperthyroidism in "susceptible individuals," >300: in addition, risk of autoimmune thyroid diseases (Andersson et al., 2007, Table 2.5, p. 14). Carpenter (2005) describes "susceptible" individuals as those who have compensated for long-standing iodine deficiency by developing goiter nodules that are dangerously efficient producers of thyroid hormones. Total goiter prevalence, i.e., the proportion of children in a population with a goiter, is an indirect measure of iodine deficiency that WHO also uses: for, respectively, none, mild, moderate and severe iodine deficiency, the lower limits for these categories are 0, 5.0%, 20.0% and 30.0%.  In addition, the WHO recommends using TSH levels, saying they are the "single best indicator" of neonatal "brain damage and impairment of intellectual development" (Andersson et al., 2007, p. 14).  Andersson et al. (2007) also note that rising TSH and T3 in combination with lowered T4 is typical for iodine-deficient populations, although all may remain within the normal range; I take this to mean that the real information is in the trend rather than in the absolute numbers.

The WHO (2008) recommends a daily iodine dose of 150 mcg, achieved by adding 20-40 mg of iodine (in the form of potassium iodide or potassium iodate) to each kilogram of salt, based on the assumption that most people consume about 10 g of salt a day.  This is about one thousandth of the dose that Dr. Coindet used in 1820, and about 2% of that used in the 1873 trial. According to the Food and Nutrition Board of the Institute of Medicine, the median daily iodine intake in the U.S. is about about 240-300 mcg/day for men and 190-210 for women, and the "tolerable upper level" for adults is 1.1 mg/day. Zimmerman et al (2005) reported that people in coastal Japan typically had a daily iodine intake of more than 10,000 mcg (10 mg).

In general, measuring iodine levels in individuals has never been part of standard medical practice, though it has been measured in research.  However, the Food and Nutrition Board of the Institute of Medicine (2001) points out that iodine deficiency can lower blood T4 and normal and/or raise blood T3, though still within their respective normal ranges.  This is no surprise: the enzymes D1 and D2 respond to this (as well as other conditions reducing T4 levels) by converting a higher proportion of T4 to T3, recycling the excess iodide ions removed in this process.  

At any rate, salt iodization had an unexpected benefit: the apparent rise of intelligence in individuals in the U.S. and its concomitant effect on social achievements.  Nisen (2003) cites a paper by Feyrer et al. (2013) that compared the American IQ-equivalent Army General Classification Test (AGCT) results from the two world wars, which had taken place before and after the U.S. salt iodization program began.  One of its key observations was that in the most iodine-deficient parts of the U.S., test scores increased by one standard deviation (15 IQ points) after salt iodization was begun. Adhvaryu et al. (2013) produced maps of rates of goiter occurrences based on WWI 1917 draft data and studied the impact of iodine supplementation and geography on high school graduation rates and participation in the workforce.  Qian et al (2005) and Bleichrodt et al (1994) also found evidence that IQs were reduced almost a full standard deviation in the most iodine-poor parts of their respective countries, i.e., China and The Netherlands.

Has salt iodization in the U.S. eliminated iodine deficiency? Dasgupta et al. (2008) mounted a convincing argument that this belief is based on false assumptions. Most obviously, fewer than half of American adults use any kind of table salt and, as pointed out earlier, processed food is rarely iodized. There was some variation in the concentration of iodine in iodized salt that they examined in freshly opened containers of salt: most (about 90%) ranged from 35 to 65 mg of iodine per kg of salt, although the range was 12.7-129 mg/kg, although most containers claim to have a concentration of 45 mg/kg. His data on the remaining contents of these containers as they are used shows a greater concentration of iodine over time. This should be no surprise, since it seems logical that the heavier iodine-containing molecules would sink to the bottom of the containers: salt, i.e., sodium chloride, has a molecular weight of 58, while potassium iodide has one of 166.

I recently bought some Morton Iodized Sea Salt. According to its list of ingredients, one-quarter teaspoon contains 25% of the RDA for sodium (590 mg) and 45% of the RDA for iodine (presumably 68 mcg). This means that enough iodized salt to meet the iodine nutrition needs of an average person would also meet about 50% of their need for sodium. Fortunately, this sodium requirement is far below the maximum sodium intake recommended by medical authorities.

But salt iodization is not the last word in iodine supplementation; at least in northern California, it appears that the public's main source of dietary iodine is multivitamin pills, each of which typically provides 150 mcg of iodine (Horn-Ross et al., 2001).

Iodine vs. key pollutants

Perchlorate Ions

Perchlorate, (ClO4-), used in the manufacturing of many products, is a contaminant of soil, groundwater and drinking water the levels of which have recently risen in the U.S.; it has come under FDA scrutiny because it can interfere with iodine uptake by the thyroid.  Although no article cited has stated this explicitly, perchlorates in general appear to be mainly water-soluble (as are iodide ions) and are apparently found in higher concentrations in food with high water content.  Accordingly, perchlorate and iodine are highest in dairy products (probably more likely milk than cheese) and higher in vegetables and fruits than they are in meat (Murray et al., 2008).

Blount et al. (2006) of the CDC sought to nail down the minimum problematic perchlorate level and determine whether iodine level, at least in women, influenced that.  These researchers developed two regression models (one for women with iodine levels < 100 mcg/L, one for the other women) to estimate the increase in TSH and T4 levels relative to the increase in urine perchlorate levels. These models involved many independent variables in addition to TSH and T4 in their model to separate all significant relevant factors.  Perchlorate levels in women in both groups had a statistically significant positive correlation with their TSH levels; in women with abnormally low iodine levels, there was also a statistically significant negative correlation between perchlorate levels and T4 blood levels; T3 levels were not studied.  This may be due to greater conversion of T4 to T3, with recycling of the removed iodide ions; this compensates for the fewer T4 molecules available from reduced synthesis and conserves iodide ions, which are recycled.

The study showed that the more perchlorate in an iodine-deficient woman's blood, the greater the corresponding increase in TSH. In the low iodine group, at one extreme, a perchlorate increase of 0.19 to 0.65 ug/L, i.e., the 5th percentile, predicted a rise of 0.23 mIU/L in those with a baseline TSH of 1.40 mIU/L, i.e., at the 50th percentile.  On the other hand, a perchlorate increase from 0.19 to 13 mcg/L, i.e., the 95th percentile, predicted a rise of 2.12 mIU/L in those with a baseline TSH of 3.11 mIU/L, i.e., at the 90th TSH percentile; results were similar but somewhat less dramatic for T4 levels. 

These regression models included other independent variables, selected for their relevance, as is standard for such models; for women in the low iodine group, those variables that were statistically significantly correlated at the p=0.001 level to T4 levels were urinary perchlorate levels (negative), estrogen use (positive), log(C-reactive protein) (positive) and total kilocalorie intake (negative).  In the high iodine group, on the other hand, perchlorate levels were not correlated (p = 0.5503) with T4 levels, while those test results that were correlated (positively, as it turned out) with perchlorate levels at the p<0.001 significance level were log(C-reactive protein) and a positive pregnancy test.  TSH results for these two groups were different: for the low iodine women, statistically significant correlations at (or near) the 0.001 level were found for urinary perchlorate (positive) and for (p = 0.0016) beta blocker use (positive), while for the high iodine women, only age in years, log(BMI) (both positive) and a "non-Hispanic black" demographic classification (negative) were statistically significantly correlated at that level. 

These results indicate that dietary perchlorate has a bigger impact on the hormones of women with lower iodine levels; this is fairly straightforward.  On the other hand, although the data on other variables suggest some intriguing relationships, one fact stands out:  The system relating TSH to T4 levels is complex and confusing from this perspective and arguably does not, by itself, provide information helpful to a treatment plan (although it provides some interesting starting points for potential studies).  Although studying underlying mechanisms was apparently the main approach of endocrinological research until some time in the 1980s, the trend today is to show the actual clinical impact of an intervention on individuals, preferably in large clinical trials. The controversy in the research world about how to treat subclinical hypothyroidism (SCH), generally defined as the coexistence of abnormally high TSH and normal T4 levels, may be fueled by the confusing messages given by such data.  

Potassium perchlorate has been used with methimazole to treat hyperthyroidism (Reichert and de Rooy, 1989).

The take-home message from this study is that, while it would be difficult to eliminate perchlorate ions from the environment, adequate dietary iodide ions would go a long way to keep it from interfering with thyroid hormone levels. 

Bromine compounds in dough conditioners, flame retardants and soda

Who would like to have a new, very reactive (but not very much fun) substance in his/her diet and/or furniture? Probably no one, but bromine compounds have made remarkable inroads into American life and getting rid of them is quite a project! 

Bromine, like iodine, is a halogen, its "upstairs" neighbor on the periodic table, does not have any proven nutritional value and has been shown to create problems.  It appears to displace iodine in the thyroid and increase the rate of iodine excretion, according to Czech research Pavelka (2004).  Although the FDA banned the use of iodine (in the form of potassium iodate (KIO3)), as a "dough conditioner," bromine, in the form of potassium bromate (KBrO3) has been allowed to stay and may indeed have been brought in to replace the banned iodine.  The FDA permits the use of bromine in baked goods, although it has established maximum amounts allowed and monitors bromine-based products. The Center for Science in the Public Interest filed a complaint with the FDA against its use (1999), and later (2005), in a paragraph within a 21-page document. Pavelka, a Czech researcher, published a literature review (2004) arguing that bromide ions replaced iodide ions in the rat thyroid; this is a matter of special concern in his country, where crop farmers use bromine products to "fumigate" crop fields between plantings.  However, Pavelka did not examine iodine deficiency at the start of the study as a factor, although that is a major problem in many European countries.

What is this "dough conditioning" function, then?  Both of these substances strengthen the dough by forming chemical crosslinks of gluten molecules, though at different times.  This is likely to be most important when a great deal of leavening takes place, enabling the loaf to keep from collapsing.  Noël Haegens (2013) describes the chemistry of bread baking in detail, and implies that only bromates will act at the important relatively late time in the dough-raising process, in contrast with early-acting potassium iodate.  So it is conceivable that before iodine was banned from the bread baking process, it might have been sometimes used in concert with potassium bromate. On the other hand, some Tasmanians replaced some of the bromates they were using in bread-baking with sodium iodate (Carpenter, 2005). I am not aware of any regulations requiring bromine to be listed as an ingredient in food, nor do I know if the listing of "dough conditioners" among baked goods ingredients implies the inclusion of bromine compounds.  There is apparently no law requiring individual "dough conditioners" to be specified in such lists of ingredients.

I personally prefer my bread lightly leavened and rather crumbly, and it is probably a good thing, too!

Another controversial source of dietary bromine in the U.S. is brominated vegetable oil, added to some fruit-flavored sodas to keep the flavor mixed in, according to Israel (2011).  The FDA monitors levels of this substance in food products, too.  On May 5, 2014, Strom (2014) reported that Coca-cola announced that it will replace brominated vegetable oil in its citrus-flavored sodas with sucrose acetate isobutyrate and/or glycerol ester of rosin. This action was apparently prompted by a 2012 petition started by Sarah Kavanaugh, who earlier successfully persuaded Pepsi Co. to remove this ingredient from its Powerade product.

Some brominated flame retardants have been found to have a toxic effect on the thyroid and liver in animal studies, according to a Swedish author (Darnerud, 2003).  The EPA (2013) is currently is working on eliminating flame retardants polybrominated diphenyl ethers (PBDEs) from the environment by discouraging manufacture and importing of such chemicals and combinations thereof because of concerns about "neurobehavioral effects;" unfortunately, there are several chemicals in this class and each requires a separate report. Part of that involves requiring the businesses involved to report any such activity. There are new organophosphate flame retardants, which unfortunately have created their own environmental problems (Salamova et al., 2013).

One general take-home message we can get from this is that banning a toxic chemical from the market is a red tape ordeal, and that finding a safe and effective one to fulfill the same purpose may be even more difficult.

Bromine has been banned from food products in California and most of Europe.

Fluorine and water fluoridation

The fluoride exposure issue has been around for a long time.  Bobek et al. (1976) showed that fluoride "administration" to rats caused a decrease in FT4, T4 and T3 blood levels in a two-month, two-dose study, although there was an increase in the T3-resin uptake ratio, a formerly used test which measures the proportion of T3 unbound to various proteins in the blood, e.g., TBG, and which might have been replaced by the FT3 test today. 

Chinese researchers have examined this issue extensively. For example, Zhao et al. (1998) discovered that iodine deficiency was associated with "dental fluorosis and increased fluorine content in the bone." More recently, Zeng et al. (2012) of the Tianjin Center for Disease Control and Prevention in China, used much more sophisticated technology to analyze metabolism in the thyroid cell when it was exposed to sodium fluoride (NaF) at four different dose levels: they determined that fluoride-exposed cells 1) were leaking more lactate dehydrogenase (suggesting structural damage), 2) had higher levels of "reactive oxygen species," 3) had a higher apoptosis rate and 4) had certain changes in the cell cycle: more time in the synthesis (DNA replication) phase, less in the growth/resting phases (G0 and G1).  The cell cycle data suggests that thyroid cells exposed to NaF were dividing more rapidly than the unexposed cells in the control group, which in turn suggests thyroid enlargement, which can lead to goiter formation.

The U.S. Environmental Protection Agency (2011) presented the results of an extensive analysis of the health risks associated with fluoride in the public water supply based on the findings of the National Research Council (2007).  The basic conclusions drawn from these documents is that fluoride added to the water supply by various products such as toothpastes has pushed the fluoride content of that water above the safety level in some places.  The focus of the EPA's document was on dental fluorosis, skeletal fluorosis and skeletal fractures; however, it apparently did not cover the influence of iodine deficiency on these conditions.

Hypothyroidism and measurement of thyroid parameters

TSH summary statistics from the Centers for Disease Control (CDC)

According to the relevant part of the NHANES III study done by Centers for Disease Control (CDC) (Hollowell et al., 2002), nearly half of the U.S. population in the "reference population" had TSH levels in the 1.1-2.0 mIU/L range and the overall TSH mean was 1.47 (Figure 1); the TSH median was 1.39 (Table 4).  Within this group, median TSH levels were 1.35 for the 12-19 age group, decreased to 1.26 in the 20-29 age group and then increased monotonically to 1.90 in the 80+ age group. Subjects in this reference group not only reported no signs or symptoms of thyroid disease but were determined by TSH (<4.5 mIU/L) and thyroid peroxidase antibody (TPO-Ab, negative) blood tests to be free of thyroid disease, but they were not 1) pregnant nor were they 2) taking estrogens, androgens or lithium.  The biggest surprise here: the "Black non-Hispanic" subset had a statistically significantly lower TSH and higher urine iodine values (Hollowell et al., 1998) than the "White non-Hispanic" subset of this group, dwarfing male-female differences.  Could this be because "Black non-Hispanic" people use more iodized salt on the average?

The "Risk Factors" population followed a more complex pattern.  Among women with risk factors (Figure 2), serum TSH values increased linearly with the age of the subjects from a mean of about 1.2 mIU/L in 20-29 age group to about 3.1 in the 70-79 age group, dropping to a mean of about 2.6 in the 80+ age group.  Although this might be interpreted to mean that the oldest women don't need as much medication, it may in fact indicate that a high TSH, i.e., over 3.0, may be life-shortening, reducing the numbers of oldest women in that TSH category.  The mean TSH of "risk factors" men followed a "U" shape over age groups, reaching its maximum at about 2.2 in the 12-19 and 70-79 age groups and its minimum at about 1.6 in the 30-39 age group.  As was the case for women in the "Risk Factors" group, their average TSH dropped in the 80+ age group; unlike them, their average TSH went down to that of the 80+ age group in the reference population. 

What is unfortunate is that no effort was made to distinguish among women with biochemical evidence of thyroid disease between the TSH values for those taking supplemental estrogen and those who were not; perhaps at that time, i.e., 1988-1994, it was assumed that most post-menopausal women were taking Prempro or a similar product and that that was medically necessary.  Since the "risk factors" population women's TSH values were significantly higher than men's only for the older age groups (50-59 through 80+), this suggests that supplemental estrogen might have been the major factor in that difference, and, had supplemental estrogen not been part of the picture, a much smaller percentage of the population might have had been classified as hypothyroid. 

The twenty-year follow-up to the Whickham Survey (1995)

This landmark study (Vanderpump et al., 1995) was notable because it showed not only the relationship between presence of anti-thyroid antibodies and TSH levels, but that, given a certain TSH level, the presence of these antibodies greatly increased the chance of the affected individual developing overt hypothyroidism, defined as a TSH measurement of at least 10 mU/L and/or obvious clinical signs and symptoms of hypothryoidism.  On the other hand, because the baseline hormone values were measured in 1975, only ten years after TSH could be measured only to the nearest 5-10 mU/L, it is not clear how precise those TSH measurements were.  But apparently overall averages are more meaningful.

But perhaps the most striking finding was the strength of both TSH and presence of anti-thyroid antibodies as predictors of the occurrence of overt hypothyroidism over 20 years.  There was an approximately 50% chance of someone with either 1) present antibodies and a TSH of about 3-4 mIU/L or 2) absent antibodies and a TSH of about 9-10 mU/L becoming overtly hypothyroid over that time period.  It's possible that the measurement precision problems presented less of a problem with comparisons than with absolute measurements because the errors in each category were about the same.

The other thyroid diseases: their influence on diagnosis of hypothyroidism

What about hyperthyroidism and thyrotoxicosis? How do views about them influence diagnosis of hypothyroidism?

Hyperthyroidism is actually a subset of thyrotoxicosis.  When levels of T3 and/or T4 that rise above the upper limit of their respective normal ranges for any reason in an individual, s/he has thyrotoxicosis.  Hyperthyroidism, on the other hand, is a type of thyrotoxicosis caused by excessive T3 and/or T4 production by the thyroid gland (Floyd, 2013); the most serious cause is Graves' Disease. This condition, caused by an apparently intractable immune system malfunction, is justly feared by physicians because of the strain it puts on the heart and because its successful treatment often requires permanent destruction of the thyroid via surgery and radiation.  At the other end of the thyrotoxicosis spectrum is a slight and temporary drop in TSH below the bottom of the normal range that sometimes occurs as a result of treatment for hypothyroidism.

Cleveland Clinic endocrinologists Pantalone and Nasr (2010) respond to what seems to be extreme physician fear of low TSH test results, however briefly present, by explaining that there are many potential causes for "subclinical hyperthyroidism," that they cause different FT4 and FT3 level patterns, and sometimes widely varying hormone levels. For example, one type of thyroid problem, subacute thyroiditis, a time-limited condition involving injury (and eventual repair) to some thyroid follicles, causes the release of the thyroid hormones in these injured follicles into the blood.  It is one of those conditions producing rapidly changing test results; therefore it can masquerade as hyperthyroidism for a short period of time.  Pantalone's and Nasr's take-home message to physicians: do not take irreversible measures until the very many (and sometimes common) possible and relatively benign causes of these scary numbers are considered and ruled out.

Evidence suggests that one reason hypothyroidism might be undertreated is that the US medical establishment regards thyrotoxicosis as not just a greater danger, but so dangerous that the risk of getting it needs to be eliminated altogether.  One compelling reason is that heart disease is apparently considered to be America's most important health problem because it directly claims the most lives, and hyperthyroidism raises that risk more obviously than hypothyroidism does.  According to Jayaprasad and Johnson (2005), hyperthyroidism raises the risk of atrial fibrillation substantially, although it still affects a small minority of hyperthyroid people, i.e., according to the U.S. Preventive Services Task Force (2004), one in 114 cases of medication-induced "TSH suppression."

CDC researchers Hollowell et al. (2002) turned up evidence that hypothyroidism is under-treated, while hyperthyroidism is not (Figure 3).  To illustrate this, they defined a "disease-free" population, i.e., all of those who self-reported not having thyroid disease (but might in fact have had "biochemical evidence" of thyroid disease).  This "disease-free" population had almost the same proportions of TSH > 4.5 mIU/L, i.e., were hypothyroid, as the total population over all studied age groups, much greater than that of the "reference" population.  On the other hand, the "disease-free" population had the same proportions of TSH < 0.4 mIU/L, i.e., were hyperthyroid, over these age groups as the "reference" population, although significantly less than those of the "total" population. 

Why would this be the case? One factor may be an independent group, the USPSTF, which states that it believes that "In general, values for serum TSH below 0.1 mIU/L are considered low and values above 6.5 mU/L are considered elevated" and that it "found fair evidence that the thyroid stimulating hormone (TSH) test can detect subclinical thyroid disease in people without symptoms of thyroid dysfunction, but poor evidence that treatment improves clinically important outcomes in adults with screen-detected thyroid disease."  Furthermore, "the potential harms of screening and treatment are principally the adverse effects of antithyroid drugs, radioiodine, thyroid surgery, and thyroid replacement therapy if detection and early treatment for subclinical disease are unnecessary."  This suggests that this group believes overdiagnosis of hyperthyroidism is potentially more dangerous than its counterpart for hypothyroidism.

There is another, less obvious, reason for physician fear of accidentally triggering thyrotoxicosis, i.e., problems with TSH assays in the latter half of the twentieth century. Until some time in the 1980s, assays were not able to measure values at the lower end of the normal range well enough for the bottom of that range to be established or for patient values to be measured with satisfying precision, long after those assays were able to produce trustworthy measurements of the top of the normal range. One way to minimize the threat of a patient's TSH going too low was to make sure that it was just below the high end of the normal range. Even today, when TSH assay precision concerns have substantially been eliminated, this concern apparently lingers, as the 2004 recommendation of the USPSTF suggests and which Pantalone and Nasr (2010) try to mitigate so vigorously.

There is hope that hyperthyroidism can be treated humanely and effectively. Antithyroid drugs that inhibit TPO expression are one form of standard treatment, and Chinese researchers (Cai et al., 2014) have shown that diosgenin limits goiter development in Graves' disease by inhibiting thyrocyte proliferation.

What about thyroid cancer, "benign" thyroid disease and iodine?

There are four types of thyroid cancer; the most common kind, papillary thyroid cancer, which accounts for about 80% of cases, progresses extremely slowly. Although two other forms of thyroid cancer are far more virulent, the overall 10-year thyroid cancer mortality rate is 4.0%, as shown by the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program data (http://seer.cancer.gov/faststats/selections.php?#Output) in Table 1. However, almost half of that mortality takes place within a year of diagnosis, perhaps mainly or entirely in patients suffering from the two most severe forms of the disease.

Table 1. Relative Survival by Survival Time for Thyroid Cancer (Click on square to see the table.)

There are some claims that thyroid cancer rates are increasing, but this essay will not take on this issue. Overall 10-year mortality rates of those with this disease are very low; in fact, the rate for those aged 20-49 years is only 1.0%, while that for those in the "75+" category is a modest 23.6%. It appears from examining these statistics that almost all thyroid cancer victims (and maybe all papillary thyroid cancer victims) die from other causes. However, since presumably all patients diagnosed with thyroid cancer are treated by having their thyroids completely removed, it is unknown how many would die of papillary thyroid cancer if they were untreated. According to Davies and Welch (2014), a reported increase in thyroid cancer was most likely caused by an increase in the diagnosis rate of existing cancers while the death rate remained unchanged; In particular, diagnoses of small papillary cancer tumors in women soared to much higher rates than those for men, even though autopsies revealed the disease to be more common in men. This discrepancy is interesting in itself, since it implies a bias toward treating women more aggressively than men for this disease.

Horn-Ross et al (2001) investigated the relationship of thyroid cancer and systemic iodine in women in northern California. They divided their sample into two basic groups, one with a history of thyroid disease (about 20% of that group) and those without ("healthy"). Their main hypothesis was that systemic iodine levels were positively correlated with thyroid cancer occurrence, but that turned out to be the case only with those with thyroid disease history. Unfortunately, because of the nature of that hypothesis, they did not feel free to conclude that those systemic iodine levels were negatively correlated with papillary thyroid cancer rates in the "healthy" group, but that was what their data implied. At any rate, this study suggested that preventing iodine deficiency in the first place would be helpful in preventing thyroid cancer in women. The problem is that women would need to find out whether they had goiters, nodules, etc. before they knew it was safe to take supplemental iodine and before a physician would be motivated to recommend doing so.

There were two aspects of this study I found especially interesting: the researchers measured iodine levels in the subjects' toenail clippings to get an estimate of long-term iodine intake, and determined that most of their dietary iodine came from multivitamin pills, each of which typically contained 150 mcg of iodine. 

The general concept of "subclinical" hypothyroidism and the special problems its definition represents in clinical research

The definition of "subclinical" hypothyroidism in clinical research is defined by lab test values and, by implication, lack of current treatment for hypothyroidism (whether or not the particular patient could have benefited from it).  Whether "subclinical" hypothyroidism should be treated is a controversial subject, but one meta-analysis (Feller et al., 2018) attempted to answer that question once and for all.  It selected 21 clinical trials from 1650 (non-duplicate) relevant studies with a T3 and/or T4 intervention on the basis of their definition of "subclinical" hypothyroidism, no concomitant medical conditions, the intervention being T3 and/or T4 administration, and of whether at least one outcome was represented in a pre-determined list of candidates.  These "endpoints" were many and varied, with the body mass index (BMI) being by far the most frequently represented, i.e., in 15 of those 21 studies.  Some others included blood pressure (7 studies), the Beck Depression Inventory (3 studies), the Underactive Thyroid-Dependent Quality of Life (2), the Billewicz score (1), as well as a variety of cognitive functioning measures.  In general, there was a very heavy emphasis on questionnaires about the subjects' feelings.  The authors noted that "no study included pain as an outcome." TSH ranges in the studies' definitions of "subclinical" hypothyroidism ranged from 3.5-10 mIU/L to 4.6-19.99 mIU/L, with some setting no maximum TSH value.  On the other hand, all made "normal free thyroxine" a requirement for that definition.  These studies were mostly small, with only two involving more than 100 subjects.  It is not clear if any of these studies measured change from baseline, which is necessary to determine the efficacy of the treatment.  Feller et al. did write: "For outcomes on which studies reported treatment effects at different time points, we included only the estimate at the most recent follow-up time point, thereby avoiding counting a study twice in a formal meta-analysis." (p. 1351)

What is interesting is that Nazarpour et al. (2018) did a validation study of the Billewicz scoring system using TSH and free T4 test result ranges as the independent variables.  So the Feller et al. study essentially did the reverse, which seems to be circular reasoning.

Feller et al. concluded that subclinical hypothyroidism was not improved by treatment from this meta-analysis.  Indeed, the calculated results indicated that the differences between those who were treated and those receiving placebo was vanishingly small.  The authors did admit that 14 of these 21 studies did not cover symptoms at baseline.  Another consideration was that subjects who were untreated at the study outset in spite of having higher-than-normal TSH values did not represent any of those who sought treatment because of symptoms.  This is a general concern that I have: no study seems to have made an effort to determine, among (untreated) patients who are deemed "subclinical" on the basis of their test results, how many sought treatment and were denied it, as opposed to those who did not seek treatment.  And among the latter, how many felt that their health was normal and how many felt sick without they themselves or their physicians suspecting thyroid disease?  Until these issues are clarified, results finding no benefit in treatment of patients with "subclinical" hypothyroidism might wrongly lead to all patients with test results in the "subclinical" range being denied treatment by government decree regardless of their level of illness.

What is also interesting is that Garber et al. (2012) in their official AACE/ATA statement say in their Recommendation 5 (assigned a grade of "A"): "Clinical scoring systems should not be used to diagnose hypothyroidism."  The Feller study depends very heavily on them in the form of questionnaires.  However, this does not necessarily indicate a conflict because the cause-and-effect nature of properly conducted RCT clinical trials allows us to measure improvements over time that can be attributed to the effects of the study drug. However, if there are no change-from-baseline measurements, results would not be meaningful; such calculations were apparently not done by Feller et al.

Hypothyroidism (both "subclinical" and "overt") and its relationship to non-alcoholic fatty liver disease

It seems logical to consider the possibility that hypothyroidism might affect the heart indirectly by influencing liver function.  Only recently has non-alcoholic fatty liver disease (NAFLD) come to be recognized as the most common liver disease, but its link to thyroid function and blood lipid problems has proceeded rapidly from in-vitro studies to a new drug which has shown promising Phase 2 results according to its developer, Viking Therapeutics (PR Newswire, 2018).

A 2010 French study (Gauthier et al.) might have provided the theoretical groundwork for that drug by identifying a plausible mechanism for thyroid hormones' blocking of fat production in the liver.  Based on the results both an in vitro and in vivo (mouse) experiment, these researchers determined a quirk of molecular geometry to be the key factor, where the binding of a thyroid hormone receptor ("Thyroid Receptor ß") to the molecule stimulating fat production, i.e., the carbohydrate-response element-binding protein (ChREBP), crowded out the binding of a liver receptor ("Liver X Receptor") because of their closely adjacent binding sites.  The starting point of this investigation was a Japanese mouse study (Hashimoto et al., 2007), which refers to "Liver X Receptor-α," apparently the molecule that Gautier et al. had referred to as "Liver X Receptor."  Hashimoto et al. were more specific in their references to thyroid hormone associated with the above thyroid receptor, calling it "T3," which presumably Gautier et al. meant.  Hashimoto et al. discovered the interference between the thyroid hormone receptor and the liver X receptor, but, unlike Gautier et al., did not propose a mechanism.

Other researchers conducted clinical research exploring this thyroid-liver relationship. Eshraghian and Jahromi, an Iranian and an Iranian-American, stated in their 2014 literature review that the majority of existing studies found a strong relationship between subclinical hypothyroidism (SCH) and NAFLD.  This literature review mentioned Chung et al. (2012), a South Korean cross-sectional observational study which involved 4648 subjects, finding a statistically significant monotonic relationship between TSH and alanine aminotransferase (ALT, the liver enzyme generally agreed to be the most sensitive indicator of liver disease) levels in subjects diagnosed with either subclinical or overt hypothyroidism. 

Chinese researchers Xu et al. (2012) responded to the Chung et al. in a research letter describing their prospective observational study following subjects diagnosed with three levels of hypothyroidism according to their TSH levels at baseline as well as a same-size group with normal TSH values over an average of 4.92 years, determining how many in each cohort developed NAFLD over this period of time.  This study found a statistically significant (p<0.05) monotonic relationship between the hypothyroidism levels and the proportion of those who developed NAFLD.

Mexican researchers Posadas-Romero et al. (2014) conducted a 753-subject cross-sectional study of initially healthy participants in an unrelated prospective study designed to ferret out relationships among subclinical hypothyroidism, fatty liver, and (as yet undiagnosed) heart disease.  Perhaps their most interesting finding given past reported results suggested that although neither fatty liver disease nor subclinical hypothyroidism alone had a significant link to coronary artery calcification, the presence of both conditions in an individual did (to a highly statistically significant, i.e., P<0.001, extent), in fact being associated with the doubling of such calcification rates. On the other hand NAFLD had a demonstrated significant link to the heart disease surrogate variables insulin resistance and metabolic syndrome even in the absence of hypothyroidism; this makes sense in the case of the latter, since an enlarged liver would contribute to waist girth, one of four problems defining metabolic syndrome.  This suggests that we should not hasten to rule out subclinical hypothyroidism as a risk factor for heart disease, even though this and previous studies have apparently not found a relationship between thyroid disease and those heart disease surrogate variables commonly measured at annual physical exams. 

Chinese researchers Yan et al. (2014) reported that a previously observed monotonic relationship between TSH levels and the prevalence of NAFLD could be explained by the presence of TSH receptors in the liver, as illustrated in a mouse study comparing those with knocked-out genes for the TSH receptor with normal mice.

Finally in 2017, American researchers tackled this question with a placebo-controlled mouse study.  At the Yale School of Medicine, Ferrandino et al. induced mild hypothyroidism in "wild type" mice with a low-iodine diet and showed that these mice gained more fat and were more like to develop NAFLD than their counterparts in the control group.  On the other hand, mice bred to have a knocked-out gene for the sodium/iodide symporter, "the protein that actively accumulates iodide in the thyroid gland," inducing severe hypothyroidism, did not develop these liver problems when fed the same low-iodine diet.  This was an especially important finding because it casts doubt on the current assumption that "mild" or "subclinical" hypothyroidism does not need treatment.

A promising development was produced by Senese et al. (2017), who report that T2 administered to rats reversed the fat increase in the liver produced by a high-fat diet by 1) reducing fat production and 2) increasing fatty acid oxidation in the liver.  Their results indicated, however, that T3 only brought about the latter change.

Hypothyroidism (especially "subclinical") and the risk of heart disease

Clinical research findings

The main issue: what questions are we trying to answer?

The AACE guidelines imply that the only justification for treating any but the most severe cases of hypothyroidism, i.e., those involving subnormal T4 and T3 values and very high TSH, is to lower the risk of heart disease. Therefore, there have been many studies of the relationship of "subclinical" hypothyroidism and both heart disease and the blood lipid values regarded by many as its main risk factors. These studies have not explored the possibility that unhealthy blood lipid values (especially those of triglycerides) and abnormal thyroid parameters may both be caused by thyroid disease.

The most obvious question here would seem to be: at what TSH level does heart disease and these risk factors appear? However, in every study of this relationship, subjects with abnormally high TSH values and normal T3 and T4 values are lumped together in one category and compared to "normal" subjects in another category with respect to blood lipid values or the presence of heart disease. One obvious problem with this analysis is that there are very few subjects with TSH values above approximately 6.0 mIU/L, even with a fairly large total subject population, and yet the range of their TSH values is quite large, with the highest (and sparsest) values typically around 15 mIU/L. One major question remains: where did the AACE's criterion value of 10 mIU/L come from?  These studies were not set up to pinpoint such a value.

Studies of the possible causal relationship of "subclinical" hypothyroidism (SCH) and ischemic heart disease (warning: your eyes might glaze over here)

Many studies have been done to examine how thyroid hormones and their deficiency affect cardiovascular health; The general consensus is that overt hypothyroidism (high TSH, low T3 or T4) does have an adverse effect on the latter, according to a literature review done by the Greek researchers Rizos et al. (2011), and the underlying biochemical reasons are well-understood. However, the consensus in the case of subclinical hypothyroidism (high TSH, normal T3 and T4) is weaker. Why is this? In order to shed some light on the discrepant results, I examined several relevant papers closely. There were differences in SCH group inclusion criteria and in the choices of independent variables: all studies used age and sex, but otherwise there were few similarities. Although this was not mentioned explicitly, the subjects who completed the studies apparently remained in normal health, requiring no medical intervention, and all had been undiagnosed with any form of thyroid disease at the outset of the studies.

Smoking status and use of "lipid-lowering" drugs presented special problems in these studies. Male-female differences in smoking status across cultures are striking here: among the Japanese (Imaizumi et al., 2004), 70% of the SCH men and 80% of the control group men reported being current or past smokers, while the respective proportions among women were 8% and 11%, while in the United States 20.5% of men and 15.8% of women reported being current smokers (CDC, 2012). Smoking status is an important variable because substances that raise dopamine levels have been shown to lower TSH levels in the short term, and in one study (Jorde and Sundsfjord, 2006) to raise T4 and T3; perhaps because of this, combining current and past smokers in this group may have been ill-advised.

Subject use of drugs such as statins prescribed to control blood lipid levels is also an important factor, since successfully lowered LDL using a statin, for instance, might mask any LDL-raising effect of hypothyroidism. Statins also have been shown to lower triglyceride levels (Miller, 2014). Therefore a study in which a higher proportion of SCH group subjects are using such drugs than that of their control group counterparts would have a reduced chance of finding higher LDL and/or triglyceride levels in the SCH group.  Does simply adding an independent variable to the model indicating whether the particular subject uses one of these drugs (or smokes, for that matter) fix this kind of problem? What seems more obvious, of course, is the down side of leaving such variables out. But let's examine the issue as we look at the studies:

Imaizumi et al. (2004) of Japan used the other independent variables systolic blood pressure, BMI, total cholesterol, smoking status, erythrocyte sedimentation rate (ESR, a test for inflammation in lieu of using the radioimmunoassay to detect anti-thyroid antibodies) and the presence of diabetes mellitus. Their study involved 257 SCH subjects and 2293 controls. The lower TSH limit for the SCH group was 5.0 mIU/L, and mean TSH values for the SCH men and women, respectively, were 7.16 and 6.57 mIU/L at baseline. They used a Cox proportional hazard model to compare the survival rates of the SCH subjects and controls at several different time points in the study; it was much greater for the men, and "nonneoplastic disease" (mostly cardiovascular disease) accounted for a disproportionate amount of male mortality. Could this have been an artifact of the large sex difference in smoking status? This suggests that men were more likely to be wrongly classified as "normal" than women, and that those men who were classified as having SCH were more likely to have a higher de facto TSH (though masked at least at times by the effects of nicotine) and a worse degree of hypothyroidism than SCH women. Yet, because past smokers were lumped together with current smokers The trial concluded that SCH was a risk factor for heart disease, but it was probably impossible to sort out the unfortunate influence of nicotine intake on the results. At any rate, Imaizumi et al. (2004) ended their article saying, "the validity of thyroid hormone replacement therapy in subclinical hypothyroidism is left for future studies."

An earlier Italian study relating SCH to blood lipid values (Caraccio et al., 2002), used a smaller group (49 in the SCH group, 33 in the control group). They recognized these pitfalls and eliminated not only smokers but all potential subjects who had any medical problems other than SCH (defined as TSH > 3.65 mIU/L, normal free T4 levels and the presence of both types of anti-thyroid antibodies, i.e., TPO-Ab and Tg-Ab) from the SCH group; these researchers also eliminated those with unstable TSH values over the six month preceding the study. Average TSH values were 1.36 mIU/L for the "euthyroid", i.e., normal, group and 5.43 mIU/L for the SCH group, with 12 women in the latter group having TSH values > 6.00 mIU/L. Using linear regression, they concluded that TSH was statistically significantly associated with low-density lipoprotein (LDL), total cholesterol and apoliprotein B, although they saw a plausible causal relationship only with LDL, which was statistically significantly higher than in controls; unfortunately they did not produce correlation coefficients.  Although the relationship of TSH and and both total cholesterol and and LDL across patients appeared to be rather weak in the graphs plotting them, there was a stronger one between those blood lipid parameters and TSH reduction during T4 therapy.  The study included a randomized placebo-controlled clinical trial involving only SCH in which the study drug was levothyroxine sodium; there seemed to be a stronger relationship between the decrease in TSH levels and both LDL and total cholesterol in patients receiving the study drug.  There also was a positive correlation with lipoprotein A (Lp(a)), although T4 therapy did not alter its values: they speculated that it represented a "genetic influence" and noted that it was closely correlated with "a positive family history for coronary heart disease and/or diabetes mellitus."

Hueston and Pearson (2004), defined SCH as having a TSH ranging from 6.70 to 14.99 mIU/L and having a T4 greater than 4.5 mcg/dL, using a 215-member sample of subjects (untreated with supplemental T4) meeting these criteria in their part of the NHANES III study; their control group consisted of 8013 "normal" subjects, so the subclinical subjects constituted 2.6% of the total number of subjects. When they compared the two groups using only TSH levels and blood lipid levels in their model, via a Student's t test (using SUDAAN to adjust for over-sampling of certain demographic minority groups), they found their HDL and LDL values to be almost identical, while the triglyceride levels of the SCH group were statistically significantly higher than those of their counterparts in the control group. However, when they altered their model by adding the independent variables sex, age, race and use of "lipid-lowering drugs," they claimed that these differences vanished when calculated as odds ratios in a relative risk model in which the original TSH and lipid variables were converted into categorical normal/abnormal variables. The adjusted relative risk for the SCH patients having high triglyceride levels was 1.83 (183% the chance of members of the control group being so), with a confidence interval of 0.87-3.85; since 1.0 was in this interval, it was deemed to be a statistically insignificant difference. However, it seems that it came very close to being significant, since 0.87 is much closer to 1.0 than 3.85 is. Besides, the defining limits of the TSH range for the SCH group seemed rather arbitrary, as was the case for the other SCH studies.  In fact, these numbers should be interpreted to mean that there is actually a much greater chance of TSH and triglyceride levels having a causal relationship than not, although TSH level trends cannot be claimed to be perfect predictors of those of triglyceride levels.

Perhaps more to the point, the application of such strict standards to a comparison of entities assumed to have no difference at all, and in which any difference should be of interest, seems wrong.  Why is the risk of concluding that there might be a causal relationship between TSH and triglyceride levels considered to be greater than than that of concluding that there is none?  Why must we set a much higher level of proof for the former than for the latter?  Even though these numbers do not prove beyond a shadow of doubt that high TSH levels might cause high triglyceride levels (or vice versa), they offer far less reassurance that there is no correlation at all.  This is important because falsely assuming that TSH levels have no effect on triglyceride levels could have serious consequences, and even more so that this is settled science, could be dangerous since it contributes to the impression that "subclinical" hypothyroidism has no complications and is therefore not a true disease, not needing treatment.

The authors attributed this shift into (borderline) statistical insignificance to adding the variable representing higher "lipid-lowering drug" use to the model, because a higher proportion of the SCH group reported using such drugs. But shouldn't this factor have had the opposite results? Had fewer subjects in the SCH group been using "lipid-lowering drugs," their triglyceride levels (and maybe even more likely, those of LDL) might have been higher, creating an even larger difference. Also, this study did not take into consideration smoking status, which may have been confounded with gender.  But taken at face value this study tells us that HDL and LDL levels are probably not an issue, and gives us a pretty good idea of where TSH levels begin to affect those of triglycerides. To be entirely fair, however, lipid-modifying drug use was an important variable and no other studies seem to have included it.

However, SCH and first heart attacks in postmenopausal women did not show a significant correlation, according to LeGrys et al. (2013).The Whickham study (Vanderpump et al., 1995), which involved 2779 apparently undiagnosed patients, had also determined that there was no relationship between "autoimmune thyroid disease" and "morbidity and mortality from ischemic heart disease. Although they did not reveal all of the independent variables that they used in their model in the abstract (which was all that was available), some others were age, "cholesterol," "mean arterial blood pressure," "smoking history" and "skinfold thickness index."

Razvi et al. (2010) reanalyzed the Vanderpump et al. (1995) data and concluded that there was in fact a significant increase of ischemic heart disease in subjects with subclinical hypothyroidism. Their analysis, using logistic regression, also involved 2279 "euthyroid" patients and 97 with SCH; the criterion range for the latter was a TSH level in the range 6.0-15 mIU/L. The non-hormonal variable values that had statistically significant differences observed across the euthyroid/SCH groups were age, sex, systolic and diastolic blood pressure, total cholesterol, and smoking status ("never," "past," and "current"). On the other hand, differences for social class (five divisions), mean weight, history of cardiovascular disease, and history of diabetes mellitus were not statistically significant. The relative risk for all ischemic heart disease "events" for the SCH group relative to the control group was 1.76, with statistical significance at the P=0.01 level, and 1.79 for fatal such "events," with statistical significance at the P=0.05 level.

Even though there was some disagreement in the conclusions that these studies drew, even the ones that concluded that there was no relationship between TSH levels and cardiovascular disease and certain of its risk factors produced results that were close to statistical significance. On the other hand, because SCH was defined so broadly in all of the studies, we are left wondering at what TSH level the risk of cardiovascular disease becomes significant. Because of this, it is hard to translate these results into therapeutic practice.

Does subclinical hypothyroidism put its sufferers at risk for any other problems? Are they less able to cope with acute infections, for instance? This would seem to be a more urgent problem than the long-term risk of heart disease.

A study of the effects of treatment of subjects with subclinical hypothyroidism (SCH) with T4 on ischemic heart disease (IHD) rates

More to the point is a U.K. retrospective observational cohort study of recently diagnosed, previously untreated subjects each with a baseline TSH measurement between 5.01 and 10.00 mIU/L (Razvi et al., 2012), which used seven years of data from the United Kingdom General Practitioner Research Database.  It concluded that this treatment was associated with a lower rate of IHD (at least for subjects in the 40-70 year age range).  The USPSTF (LeFevre, 2015) regarded this study with special favor because it gave information on whether treatment actually worked.  On the downside, however, this study did little to establish a threshold TSH at which T4 treatment was helpful, although it challenged the hypothyroidism treatment threshold TSH level of 10.00 mIU/L, apparently currently in effect in the U.K.

I was concerned about his conclusion that treatment did not help the subjects in the 70+ age group, especially given that the subjects in this group selected for treatment had higher baseline values for TSH and BMI than those on placebo at the statistical significance level of P<.001. (This was true of the other age group for just TSH.) In addition, no consideration in the experimental design was given to whether any subjects were taking statins to control their total cholesterol levels (although values for the latter were considered during randomization.)  The morbidity/mortality hazard ratios for the seven groups of disease considered across the 70+ group clustered around 1.00, while those for the 40-70 age group averaged 0.60, favoring the treated subset.  What was especially interesting is that treated subjects in both age groups had a much lower rate of "malignant neoplasms."

Two Possible mechanism linking SCH and "bad" blood lipid levels

Rizos et al. (2011) in their literature review cite studies which conclude that T3 1) sensitizes LDL receptors, which limit the production of LDL, 2) stimulates the activity of lipoprotein lipase, which breaks down harmful lipoproteins and 3) upregulates apoliprotein AV, which reduces triglyceride levels. Since T3 levels are normal by definition in SCH patients, the latter would not be expected to have their blood lipid levels affected by these mechanisms. So where could be the underlying cause(s) of worsened blood lipid profiles in SCH patients?

It might be that infection is the causal link: infections of parts of the body other than the thyroid may stimulate TSH production and worsen blood lipid profiles in ways that suggest higher risk for cardiovascular disease. According to Varghese et al. (2008), viral infections (by the T3D reovirus) may cause TSH synthesis in intestinal epithelial cells. On the other hand, Apostolou et al. (2009) showed that acute brucellosis infection  was associated with an "atherogenic lipid profile" up to four months after recovery from the infection, and cited analogous studies associating cytomegalovirus, Chlamidia pneumoniae, and Helicobacter pylori with such a profile. 

But are hypothyroid patients especially susceptible to infection? There is a remarkable deficit of research on this subject, even though it is well-known that hypothyroidism typically causes cold intolerance and it is generally accepted that fevers stimulate the immune response (Nalin, 2005). However, one physician in a landmark book on hypothyroidism devoted a chapter to his dawning realization of a tendency for hypothyroid patients to get infections much more than healthy people, and for treatment of the hypothyroidism to lessen the occurrence of infection in these people (Barnes and Galton, 1976, 86-100).

Kolata (2016), a science writer, discovered some relevant knowledge at the Institute of Diabetes and Digestive and Kidney Diseases that hadn't been shared widely: what causes insulin resistance (and apparently bad blood lipids) was a shortage of fat cells relative to an individual's need to store unused dietary energy. The number of these cells does not automatically increase when one's dietary energy increases, although the individual cells might be able to expand in size to a limited degree. When there is no more room in the fat cells, the fat has to be stored elsewhere in the body, such as the liver and several other vital organs, causing the various manifestations of "metabolic syndrome." Perhaps when people experience the sudden weight gain frequently associated with hypothyroidism, the excess dietary fat goes to these parts of the body, producing the laboratory test results associated with this syndrome.

One reason that SCH might cause higher triglyceride readings and perhaps LDL in blood test results is that people with hypothyroidism digest food more slowly and may not succeed in emptying their stomachs before being tested. There seems to be a lot of controversy today about whether nonfasting triglyceride levels are as meaningful as their fasting counterparts and even about the magnitude of the impact of (measured) triglyceride levels on heart health, but wide differences in digestion rates may be muddying the waters. Since ultrasound technology can be used to determine whether an individual's stomach is indeed empty, the means exist to determine this experimentally and therefore to sort out these issues. I hope this will eventually be done.

Another confounding factor may be the fact that a high TSH in some types of people may not indicate hypothyroidism, subclinical or otherwise: as discussed later, those engaging in heavy exercise and therefore most likely to have good blood lipid values may drive their TSH levels higher, perhaps out of the normal range. Maintaining such high levels of exertion may eventually do permanent damage to the thyroid (and apparently no research has been done on this), but it may take years for this to happen.  In any case, researchers have not explored this issue to my knowledge.

The impact of estrogen levels on thyroid health, and implications for pregnancy, infertility and breast cancer

Clinical research: the relationship of estrogen levels to thyroid performance

Estrogen levels have an impact on thyroid health and even "subclinical" ("mild") hypothyroidism in pregnant women can cause their babies to be born prematurely and have lowered IQs.  Although the relationship of TSH levels and goiters to pregnancy outcomes has long been known, more recent research has shown that iodine transport and metabolism may explain this: do the thyroid and the parts of the body directly involved in pregnancy compete for iodine?  But there are really two separate questions we need to answer: 1) which problems are caused by iodine deficiency? and 2) which diseases can be successfully treated by using iodine as a drug?

An early study (Sawhney et al., 1978) of rhesus monkeys measured TSH increase when 50 mcg/kg of estradiol was administered; over 28 days it increased from an average of 1.4 to 3 mIU/L, where it plateaued.  The authors concluded that a reduced rate of TSH degradation, presumably by the liver, was responsible rather than an increase in TSH production by the pituitary gland. 

Furlanetto et al. (1999) discovered that estradiol, the most potent estrogen, "down-regulates the sodium-iodide symporter gene" in the thyrocytes. Tazebay et al., 2000 added that a local sodium/iodide symporter "mediates active iodide transport" only in the lactating or cancerous breast.  Stoddard et al. (2008) suggested that inorganic iodine may provide protection against the development of breast cancer, reporting that in vitro treatment of a line of human breast cancer cells with a solution containing 5% molecular iodine (I2) and 10% iodide ions (I-) in the form of potassium iodide (KI) caused up-regulation of genes causing estrogen breakdown and down-regulation of genes stimulated by estrogen.  However, it is also possible to draw the conclusion that at least one of these forms of iodine is necessary for breast growth. Is it possible that estrogen acts on these symporters in a way that routes iodide away from the thyroid and especially toward the breasts, at least during lactation and in the case of breast cancer?  If so, can the breasts get too much iodine with treatment for hypothyroidism?  And what effect does iodine have on them?

A finding with important therapeutic implications was the Eskin et al. (1995) rat study, which sought to distinguish between the breast tissue effects of I2 and I-:  According to several measures of breast pathology, i.e., "lobular hyperplasia," "extraductal secretions" and "periductal fibrosis," the presence of I2 was either beneficial or neutral, but harmful or neutral in the presence of I-.  These findings were supported by Garcia-Solis et al. (2005), who found evidence that I2 showed that the magnitude of the in vitro anti-cancer effect was strongly correlated with gene expression of the ion exchanger pendrin, a iodide/chloride (I-/Cl-) "transporter," which transfers I- from the thyrocyte to the colloid in the thyroid and performs an analogous function in other locations in the body, and inversely correlated with gene expression of lipoperoxidation, i.e., reacting of peroxides with fat in the tissue.  Notably, there was no change in the gene expression of the Na+/I- symporter, which brings I- from the blood into the breast and thyroid cells.  Garcia-Solis also drew the conclusion that I2 (but apparently not I- or T4) reduced tumor incidence in rat mammary tissue, and that this was associated with an antioxidant effect.  Funahashi et al. (1996) agreed that "inorganic iodine," perhaps a combination of I2 and I- (but not specified in the abstract) suppressed breast tumor growth in rats, but medroxyprogesterone acetate (MPA) had a stronger effect, and the combination of the two was even stronger.  They concluded this because the degree of tumor suppression in the rat tissue was correlated with the magnitude of iodine concentration (four different dose levels) in that tissue.

These were troubling findings, since the form that the thyroid uses, and which is available to the consumer, is I-.  But I wish they could explore the reasons for the different effects these two forms of inorganic iodine have on the body.

Arafah (2001), who studied estrogen and progestin supplementation (HRT) in women, suggests that increased TSH in pregnancy can be explained by 1) TBG increase, 2) degradation of thyroid hormones by the placenta, 3) transfer of T4 to the fetus and 4) increased maternal excretion of T4.  This paper reported the results of a prospective observational study involving 11 normal women, 18 with benign, i.e., non-cancer, thyroid disease and 7 who had been treated for thyroid cancer who were each given 0.625 mg of "conjugated estrogens" daily and maintained on their baseline dose of T4.  In women with normal thyroid function, TSH varied very little, staying between 1.0 and 2.0 mIU/L, while the TSH in women treated for hypothyroidism jumped from an average of about 1.5 mIU/L at baseline to one of almost 4.0 at 12 weeks, although it quickly dropped down near original levels at around Week 18.  However, these averages disguised a great deal of variation; some of the TSH values for the subjects with benign disease went above 10.0 while others remained below 1.0.  On the other hand, T4, FT4 and TBG values did not vary significantly across these various groups.

Demonstrating that an existing "normal" range is too wide requires taking unfortunate measures which, although within the ethical rules of clinical trials, are perhaps too imprudent to state openly.  Yet some clinical trials have effectively done this for pregnant women with hypothyroidism, though their stated goals were to show that their subjects needed an increase in T4 supplements.  Unfortunately, because of increasing pressure to adhere to official standards, this unfortunate measure has become necessary to reform those standards.

Alexander et al. (2004) concluded that an increase in levothyroxine was necessary for pregnant women with hypothyroidism. They performed a clinical trial involving pregnant women, fourteen of whom had hypothyroidism caused by benign conditions, i.e., either Hashimoto's disease, treatment for Grave's disease or a benign thyroid nodule, and six of whom had been surgically treated for thyroid cancer, using levothyroxine replacement therapy at levels intended to "suppress" TSH levels, i.e., to keep them minimal.  The authors stated that T4 dose was increased for the fourteen when TSH went over 5.0 mIU/L, and over 0.5 mIU/L for the six.  These women had been maintained before entering the study at TSH levels far below this maximum, arriving at the start of the study with a baseline average of 1.53 mIU/L for the  fourteen subjects with "benign" disease and of 0.06 mIU/L for the other six treated for thyroid cancer.

During the study, however, their TSH levels were allowed to rise much higher.  At eight weeks, the average TSH for the entire group (which included six thyroid cancer patients who in theory needed to have their TSH levels kept below 0.5 mU/L), rose to a mean of 4.2 mIU/L, with a standard deviation of 3.8 mIU/L.  Percent increases in thyroxine dose averaged 35% for the fourteen and 48% for the six. Of the fourteen patients, two pregnancies ended abnormally, one with a miscarriage and one with a stillbirth (though neither patient had Hashimoto's disease); one thyroid cancer patient had an induced abortion.  The rise in estradiol levels in pregnant women is very large: in this study, they rose, on the average, from somewhat less than 50 pg/ml to about 10,000. 

Maraka et al. (2017) performed a retrospective cohort study of pregnant women with TSH levels in the range of 2.5-10.0 (my interpretation, although the authors wrote it as "10," improperly according to my understanding) mIU/L, 16% of whom had been treated with supplemental levothyroxine. They divided the group into four cohorts, depending on whether they were treated during the study and whether their TSH levels fell in the range of 2.5-4.0 mIU/L or in the range of 4.1-10.0 mIU/L in order to determine the differences in health outcomes that could be explained by the treatment. They concluded that among those in the two cohorts, pregnancy loss was less in the treated women than in the other cohort at a significance level of P<0.01, although this significance was not present in the lower pre-treatment TSH group. On the other hand, the treated group had more medical problems, most notably preterm delivery at a significance level of P=0.01; this significance was not present in the high pre-treatment TSH group. Only one medical problem affecting the women themselves, gestational diabetes, was significantly increased (marginally) in the higher pre-treatment TSH group, while gestational hypertension and pre-eclampsia were significantly increased in the lower pre-treatment TSH group. One shortcoming of the study is that it did not distinguish the patients' conditions and TSH by trimester; this matters because the unborn child does not have a functional thyroid during the first trimester, putting more stress on the pregnant woman's thyroid.

Estrogen and the hypothalamus: in vitro studies

Estrogens, like all small nonpolar molecules (including other steroids), pass through the cell membrane without resistance and bind to a receptor that triggers gene expression. However, recent research (Qiu et al., 2003) on the effects that estradiol has on the hypothalamus' arcuate nucleus shows that estradiol also has a quicker-acting mechanism, similar to that of the action of the nervous system, by which it binds to receptors cells on the cell membrane, which activate a G protein, via the diacylglycerol metabolic pathway.

The impact of non-thyroid diseases on thyroid test results and possible HPT axis hormone treatment

Critical illness, i.e., "low T3 syndrome" and stages on the way

In a nutshell, if a disease persists in a part of the body other than the thyroid, the TSH rises, sometimes out of the normal range.  But as its severity increases, TSH levels go back down, and so do those of T4.  However, a decrease in T3 levels is temporarily staved off by the increasing adaptive conversion of T4 to T3.  If the disease is so severe that net catabolism (breakdown of tissue) becomes established, then T3 falls steadily, and its progress downward below the normal range is considered to be a strong predictor of imminent mortality (Mebis and van Berghe, 2009).  This means that at some stages of yet-undiagnosed non-thyroid disease, some patients would be officially considered to have "subclinical" hypothyroidism, if indeed they had their TSH levels tested. Should a slightly elevated TSH be considered a red flag, an early warning that something else is going wrong? Since the findings of Varghese et al. (2008) indicate that viral infection can stimulate the production of TSH outside the normal HPT axis, this is worthy of investigation.

TSH levels aren't necessarily the most sensitive indicators of conditions that might benefit by being treated with supplemental hormones in the HPT axis. The exceptions are generally found in "critically ill" patients, i.e., with catabolic illnesses; they are so ill with a disease affecting another part of the body that they experience persistent protein loss.  According to the Adler and Wartofsky (2007) literature review, levels of the thyroid hormones, especially T3, are the best indicators of the severity of a patient's serious, acute non-thyroid disease and its prognosis.  They discuss the D1 iodothyronine deiodonase (though not as such) and its activity in the liver.  They suggest that such a seriously ill patient, i.e., one with "deteriorating clinical status" who has "test results suggestive of hypothyroidism" might benefit from intravenous T3 infusion.  On the other hand, they recognize that many non-thyroidal diseases can induce "so-called subclinical hypothyroidism," i.e., high TSH and normal T4, and believe patients with this pattern should get the standard treatment for hypothyroidism.

Adler and Wartofsky considered infectious disease (HIV and sepsis), diseases of the heart (MIs, unstable angina, acute coronary syndrome and heart failure), kidney (nephrotic syndrome and end stage renal disease) and liver (cirrhosis, acute hepatitis and chronic liver disease).  However, they did not consider non-thyroid cancer or diabetes, two diseases which often make enormous energy demands on patients.  They do consider the thyroid side effects of several classes of drugs when used in "critical illnesses," most notably "stress doses" of corticosteroids and intravenous dopamine; both induce central hypothyroidism, i.e., caused by malfunction in the hypothalamus or pituitary gland, reducing TSH, T4, T3 greatly and free T4 somewhat less.

Belgian researchers Lambert et al (1990) studying AIDS patients found a strong negative correlation between CD4 lymphocyte count and TBG levels, but not with those of cortisol-binding globulin (CBG) or sex hormone-binding globulin (SHBG).

Haugen (2009) did a more exhaustive run-down of the effects of various drugs on TSH and the thyroid hormones. One drug of special concern to those who treat thyroid disease is amiodarone, which is used to treat heart arrhythmias and contains iodine.

Since the liver produces TBG, and D1 to convert FT4 to T3, thyroid parameters in liver disease patients depart from the usual pattern described above. Borzio et al. (1983) tried to answer this puzzling question: why, in spite of the important role the liver plays in thyroid hormones metabolism, and the dramatic reduction in T3 seen in cirrhosis, does liver disease usually not cause clinical hypothyroidism symptoms and signs?  Their answer was very elaborate, but this is how I read the narrative of their data: TSH rises to an average of 3.1 mIU/L in cirrhosis patients and 2.7 mIU/L in hepatitis patients, in contrast to 2.4 mIU/l in controls, which contributes to a high FT4 (an 11.9 mIU/L in cirrhosis and chronic hepatitus patients, respectively) in contrast with that of controls (9.9 ± 0.3 mIU/L).  As a result, the FT3 of cirrhosis patients was 69% of that of controls, a striking improvement over the analogous ratio for total T3 values (56%).  Since the liver's production of TBG would seem to be reduced in liver disease, that would be an obvious suspect; however, TBG was in fact higher in the liver disease patients than in controls.  One possible explanation for this is that a decrease in liver function causes a rise in estrogen levels because one role of the liver is to break down estrogen; estrogen has been shown to cause TBG levels to rise.  In fact, the effects of rising estrogen levels, and by extension pregnancy, on thyroid parameters and overall health is a very heavily studied topic, which I will soon discuss in more detail.

Mebis and van den Berghe (2009) produced a more sophisticated analysis, which involved a close examination of the roles of the three thyronine deiodinases (D1, D2 and D3); Each of these enzymes removes an iodide ion from T4 (not always from the same location in the molecule) to produce what is sometimes a useful new molecule.  In health, the D1 iodothyronine deiodonase, mainly located in the liver (which sends its products to other parts of the body), is dominant, converting T4 into T3; in both acute and prolonged "critical illness," while the D3 iodothyronine deiodinase converts T4 into nonreactive reverse T3 (rT3).  The D2 iodothyronine deiodonase, like its D1 counterpart, converts T4 to T3 but is found in other tissues, i.e., the brain (80%) and skeletal muscle, operates only locally and appears to be upregulated in hypothyroidism.  Understanding of the roles of these enzymes in critical illness was necessary to pin down the body's elusive compensatory mechanisms under these conditions, and to determine, which, if any, hormone supplementation regimen could provide effect support to these patients' recovery processes.

Mebis and van den Berghe (2009) challenged what they saw as a prevalent perception that low T3 syndrome (especially "reduced expression of TRH in the hypothalamus") was "adaptive and beneficial" rather than an aggravating factor or a red flag in "critical illness" calling for medical intervention.  The compelling mystery here is why critically ill patients have low thyroid releasing hormone (TRH) and low blood T3 and T4; iodothyronine (a component of T3 and the Dx enzymes) is likewise very low.  The authors reject these possible theories of how this combination of conditions in critically ill patients mitigates their danger with these arguments: 1) descending T3, typically occurring during progressive protein catabolism (disintegration) in critical illness, is obviously not adaptive, 2) high cytokine levels, because they were shown not to correct defective T3 and T4 levels, while cytokine antagonism alone likewise failed to help and 3) upregulating levels of T3 receptors, found in the "oldest and sickest" patients, is a natural response to declining T3 levels, but not an effective one in the end. 

A key study (Baur et al., 2000) concluded that D1 (mostly in the first hour) and D2 (more slowly, over at least 24 hours) were both upregulated when put in direct contact with some cytokines stimulated by the injection of lipopolysaccharides (LPS) into rat anterior pituitary tissue, whether in vivo or in vitro; however, in vivo, D1 in the liver remained constantly slightly lower and less variable in tissue receiving the LPS injection than in control tissue.  This supported the theory that local hyperthyroidism in the anterior pituitary gland caused by upregulation of D1 and D2 in turn caused by heightened immune system activity in that gland led to systemic hypothyroidism caused by the compensatory downregulation of D1 in the liver, in term lowering its conversion to T4 to T3. This local hyperthyroidism would trigger a drop in TRH production.  Therefore, Mebis and van den Berghe (2009) reasoned in their literature review, a compensatory infusion of TRH could improve such patients' survival chances. They refer to a study (Van den Breghe et al., 1998) in which they explored the use of infusions of different combinations of TRH and at least one of two substances stimulating growth hormone secretion, i.e., GH-releasing peptide-2 (GHRP-2), and growth hormone releasing hormone (GHRH) with acutely ill patients in an intensive care unit (ICU) in a trial with a complex crossover design: they concluded that HPT axis hormone levels were probably thrown off by the illnesses that put the patients in the ICU and could be jump-started by infusions of these hypothalamus hormones.

Wu (2000) states that thyroid disease is much more common in diabetes patients than in others, that in fact 30% of female type 1 diabetes patients have thyroid disease, and that 36% of all diabetes patients have hypothyroidism.

Unresolved questions: differing value systems and problem-solving based on them

Controversies persist in part because the necessary technology has only recently been developed, while many landmark studies used what is now obsolete technology.

Determining the TSH reference range, one of two criteria used for diagnosis: as much art as science

Medical authorities in both the United States and Europe seem to agree that TSH levels are the way to diagnose (or rule out) primary hypothyroidism, although they acknowledge that urine iodine levels, thyroid size (as a measure of iodine nutrition) and (to a lesser extent) antithyroid antibody levels are important concerns.  The usefulness of urine iodine levels is limited because it reflects only very short-term nutrition: the Food and Nutrition Board of the Institute of Medicine (2001) states that it reflects iodine intake over only a few days.  Thyroid size may reflect iodine deficiencies that were eliminated in the distant past, leaving their mark as necrosis-induced swelling as discussed above; Brabant et al. (2006) noted that the upper limit of a TSH reference range calculated for an eventually successfully treated population in an iodine-poor area was lower than for other populations without that problem, suggesting that residual goiters in those with currently adequate iodine nutrition and normal thyroid function caused them to be excluded from the "normal" population.  Antithyroid antibodies also have an obvious limitation: results are reported simply in terms of their presence or absence rather than in terms of counts (for reasons I don't understand), so these results cannot influence the dose of medication prescribed.

But is the TSH level is necessarily such a straightforward indicator of this disease?  Many factors irrelevant to thyroid health can affect TSH levels, giving misleading readings; as Brabant et al. (2006) admit, they include "acute stress," exercise, non-thyroidal illness, nutritional factors (most notably iodine), drugs, i.e., dopamine and glucocorticoids and estrogen levels.  To add to the confusion, there are several different forms of TSH (Demers and Spender, 2002) and of human chorionic gonadotropin (hCG), which rises sharply during pregnancy, and the structural similarities are such that one form of hCG has been determined to have a strong affinity for TSH receptors; as a result, a certain amount of this hCG form can result in clinical hyperthyroidism (Yoshimura et al., 1993).  

One major measurement problem seems to be that TSH so reliably and quickly increases as a result of known sources of stress that it is, in the short term, a de facto measure of stress.  There are also some long-term causes of stress, of which thyroid disease is just one.  Non-thyroidal disease also causes TSH-raising stress, maybe sometimes more than a "normal" thyroid can handle.  Adding to the confusion are other known forms of TSH-raising stress, which include pregnancy, difficult life passages such as menopause or adolescence, sleep deprivation, exposure to cold, estrogen supplementation (or abnormally high levels), a great variety of drugs, and, most controversially and lightly studied, "healthy" physical activity.  Some hormones and neurotransmitter agonists interact with TSH in other, sometimes complex and confusing but perhaps medically important ways, most notably cortisol, growth hormone, anabolic steroids (presumably androgens) and dopamine (notably in smokers).  Melatonin, the sleep-inducing hormone, appears to be closely regulated by TSH in conditions of darkness.  To add to the confusion, TSH levels apparently change very rapidly as stress levels change, perhaps governing circadian rhythms although they apparently stay below certain levels in normal people engaging in typical activities.

In the United States, the medical establishment has decided on a simplified approach for determining thyroid health, including iodine sufficiency, as summed up by the Institute of Medicine, Food and Nutrition Board (2001).  It considered three possible measurements of thyroid performance: 1) Urine iodine levels, 2) thyroid size and 3) TSH levels.  Urine iodine level measurement reflects only very recent levels in the body; therefore it was dismissed.  Goiters (apparently because of the role of thyrocyte necrosis, as discussed above) can become permanent, even after normal thyroid hormone levels were restored, therefore thyroid size was dismissed.  TSH measurement remained, described as the most sensitive measurement of thyroid health and iodine sufficiency, reflecting long term conditions, and the proposed normal range was 0.5-6.0 mIU/L.  This may be due to the recommendation of the U.S. Preventive Services Task Force, a group of medical care providers, mostly practicing physicians, that serve in an advisory capacity to the U.S. Congress in medical care policy matters: in a 2004 document, they said that they considered the normal range of TSH to be 0.1 - 6.5 mIU/L.  On the other hand, the National Academy of Laboratory Biochemists (NACB), the "academy" of the American Association of Clinical Chemists (AACC), is turning the subject over; Demers and Spencer (2002) presented a document to the NACB that recommended 0.4 - 4.0 mIU/L as a "reference" range for adults, apparently the most recent such document available to the general public.

Many European studies have been done recently reexamining the conventional reference ranges for TSH and thyroid hormones just in the last ten years.  Arriving at these decisions is a complicated process involving many difficult judgment calls.  As an example, I chose to examine Kratzsch et al. (2005) closely because of their conscientious and detailed reporting of their decision-making process and honest expressions of concern about its correctness afterward.   Starting with a group of "apparently healthy" blood donors ("whole group"), they eliminated those who 1) had a personal or family history of thyroid disease, 2) had anti-thyroid antibody counts above a certain low level deemed to be natural in healthy people (determined from another more strictly selected group) and 3) had a goiter and/or thyroid nodules as determined by ultrasonography to produce the "constraint group."  The conventional step from here would have been to transform the "constraint group" into a normal distribution, to determine the mean and to eliminate group members with relevant test values more than two standard deviations from the mean, i.e., about the outer 5% of this group at both tails of the curve.

But there were two issues Kratzsch et al. wanted to resolve: 1) the inability of the new truncated distribution of the "constraint group" to be transformed into a normal distribution and 2) the existence of independent non-disease discrete variables that bore a statistically significant relationship to TSH.  So this team decided to establish separate reference ranges for individuals who had different values for these non-disease discrete variables, which they determined to be sex and oral contraceptive use for their statistical model, a "stepwise forward multiple regression" instead of a single-step multiple regression.  They did not use interaction variables, understandable in a model with eight independent variables.  Unfortunately, age (range 18-68 years, average or median? for men and women, 32.4 and 30.6, respectively) and contraceptive use probably did interact, i.e., had a kind of negative correlation: women on oral contraceptives tend to be younger than those not on them, and higher TSH levels have been shown to be linked to both estrogen supplementation and greater age.  This perhaps explained why Kratzsch et al. found that TSH in the "constraint group" decreased slightly with age (represented as a categorical variable with one cutpoint at 40), perhaps because of the influence of oral contraceptive use in the younger group, leading to the unusual pattern in the two new derived reference ranges for women: the median TSH for women on contraceptives was higher than that for the other women, i.e., 1.56 vs. 1.29, but the upper limit of the reference range (the 97.5th percentile) for those on oral contraceptives was lower, i.e., 3.50 vs. 4.25.  As a result, Kratzsch et al. concluded that there was no significant difference in TSH between women on oral contraceptives and those not on them.  On the other hand, this odd pattern did not show up with T4 and T3, which were clearly higher for the women on oral contraceptives, while their free T4 appeared to be practically identical. This suggests that the TSH values for women on oral contraceptives represented different levels of nudging of the thyroid by the pituitary, depending on the thyroid's performance, with T3 and T4 levels, not free T3 and free T4, providing the relevant feedback to the pituitary; this would make sense because oral contraceptives have their effect on thyroid performance by increasing thyroid-binding globulin (TBG), which acts on T3 and T4 to determine free T3 and free T4.

Using Roche's Elecsys radioimmunoassay system, Kratzsch et al. came up with an upper limit of 3.77 mIU/L for the TSH of the constraint group (a little higher than the one calculated for the "whole group.")  They also mentioned in passing that they calculated an upper limit of 2.92 mIU/L for that same group using Bayer's "Centaur method."  They concluded that the general consensus seemed to be that the upper limit of the TSH reference range was somewhere between 2.5 mIU/L (the NACB's recommendation) and 4.0.

Zöphel et al. (2006) commented that Kratzsch et al. might have done well to have considered urine iodine levels or deficiency as a variable in their model, pointing out that a previous European study developing a TSH reference range had found a relationship between higher TSH and greater iodine deficiency and implying that ultrasonography cannot distinguish between endemic goiters and those caused by primary thyroid disease.   Zöphel et al. also pointed out that the discrepancies between the results from the Electrosys and Centaur systems may have been due to variations in the epitopes of the TSH molecule, causing it to interact differently with the antibodies used by different brands of radioimmunoassay equipment.  Finally, Zöphel et al. displayed a graph from their 2005 paper, showing a sharp drop in the frequencies of TSH values down to 4.0 mIU/L for four different groups, i.e., 1) the reference population, 2) all participants, 3) people positive for antibodies and 4) those with a "hypoechoic pattern in thyroid ultrasonography," i.e., without a goiter or thyroid nodules. Each of the curves peaked sharply at about 1.1 mIU/L and dropped almost linearly to the point at which TSH was equal to about 2.5, with the exception of the "hypoechoic pattern" group, which showed less overall variation and was still quite low in frequency at 4.0 mIU/L.  In a nutshell, all involved parties (at least on the European front) agreed that a TSH of 4.0 mIU/L was clearly abnormal and one of 2.5 was quite unusual.

If there is one thing you the reader take away from this reference range description, it should be that determination of the "normal" or "reference" range is a complicated process requiring many difficult judgment calls, and the different results that currently available assays produce call into question the precision with which the limits of this range can be established; the problem is not so much one of chemical analysis correctness, but also of physician judgments of the health of past patients.

The one approach to the reference range/normal range problem that I would like to see, and which has not been considered, is a regression model with TSH as the dependent variable and other relevant parameters such as anti-thyroid antibody presence (levels?), urine iodine level(s), dopamine agonist (caffeinated beverages, nicotine) use, corticosteroid use, estrogen use and levels, hCG levels, exercise levels and perhaps some other factors that Blount et al. (2006) used in their perchlorate model and Mutaku et al. (2002) in their goiter model.  This way it would be possible to determine the relative impact of these factors on TSH levels. 

It is important to note, as discussed above, the tendency of dopamine agonists to reduce levels of TSH and the thyroid hormones; not only would heavy use of these substances tend to mask hypothyroidism, but individuals with untreated hypothyroidism might be more likely to self-medicate with them to compensate for the loss of the natural stimulating effect that thyroid hormones provide.  They might not be aware of the special problems these stimulants present because of their tendency to aggravate their condition.

What about the stress of exercise (and staying up late) in healthy subjects?

Would strenuous exercise would put stress on the thyroid, perhaps raising TSH levels to an unhealthy extent?  This is important not simply because years of overexercise (which may be becoming more and more popular, especially in some municipalities) might cause permanent damage to the thyroid, but because those engaging in this practice are likely to be seen as especially healthy, thereby unfairly raising the upper limit of the TSH reference range, locally, if not globally.  How can we tell how much is too much, and keep this factor from making it more difficult for others who have genuinely diseased thyroids to be diagnosed?

There are a very few studies touching on this subject of exercise as TSH-raising stress while focusing on the impact of sleep interventions on circadian rhythms.  Van Reeth et al. (1994) first measured the impact of physical exertion on TSH levels over time as part of an ambitious study seeking to develop a regression model involving several hormones to predict circadian cycle phase shift changes caused by exercise undertaken near midnight.  The authors were surprised by the results: "unexpectedly, exercise had robust stimulatory effects on plasma TSH levels."  This study using 17 young, "healthy" men with a clean lifestyle and who had followed normal sleep schedules before the start of data collection.  Although the subjects "had no personal history of ... endocrine illness," Subject 11, one of two subjects whose TSH data were featured in graphs, had TSH values that soared to about 5.0 mIU/L in the baseline (continuous bed rest) study and rose up to almost 8.0 in the exercise study at the end of the exercise period.  In contrast, the TSH values of Subject 14 (a much more "normal" subject according to the previously discussed CDC data) spiked up to about 2.2 from about 1.8 during the baseline study during the after-bedtime period (and was lower during the day) and ranged from 2.5 to 2.9 during the exercise period in the other study.  Unfortunately, the researchers merely regarded the "unexpected acute effect of exercise" on the TSH curve as a problem for the regression model, one that fortunately could be overcome only because TSH levels were already on the rise before the exercise period; no overall TSH statistics over time were presented).  In fact, as a result, it was hard to sort out TSH values as a separate factor.  Perhaps the most interesting thing to come across clearly and emphatically was that TSH and melatonin levels appeared to dovetail very closely, with the TSH leading.  In fact, these results suggested that TSH levels may govern circadian rhythms, which seem to be the logical outcome of the body's available energy.

Leproult et al. (1997) introduced the psychological factor "sleepiness" and found that, in subjects who stayed up late at night it had a strong statistical relationship to the levels of the hormones that Van Reeth et al. (1994) had studied and body temperature.  Specifically, they observed that increasing "sleepiness," "decreasing body temperature, rapidly rising cortisol concentrations, and maximal levels of melatonin and TSH" occurred together based on a study that simply involved bed-rest without sleep; however, in the part of the study involving a 3-hour period of exercise, they only studied the relationship of the "sleepiness" measurement to melatonin levels.  However, they made mention of the "sleep-facilitating effects of corticosteroids" supported by this study and by others, and speculated that "continuously rising cortisol levels and the persistence of high concentrations of TSH and melatonin may have contributed to increased subjective fatigue."  Unfortunately, the absent TSH data during the exercise study deprived this study of much interest for those interested in this issue.  On the other hand, Fig. 2 showed that the maximum TSH for these subjects was three times that of the minimum during the baseline (bedrest) study.

Scheen et al. (1998) performed a study that focused on the impact of exercise on TSH levels.  They measured the TSH values of each subject over a 24-hour period, during which a 3-hour exercise period was scheduled at one of three different times of the day, i.e., the morning, afternoon and around midnight.  During the time of the day that the subjects logically would be most tired, e.g., at bedtime, their TSH levels increased almost 100% near the beginning of this exercise period over their pre-exercise values, staying at about that level throughout the exercise and dropping gradually afterwards.  TSH rises were much smaller during the morning and afternoon (up to only about 50% of pre-exercise levels) and returned to those pre-exercise values much sooner.  Unfortunately, only relative, not absolute, TSH values are reported in this article, but it does show that TSH can be elevated a certain amount by exercise, and given what Buxton et al. (2000, Fig. 3) have discovered about TSH at rest, i.e., that a TSH of about 1.5 mIU/L is the maximum to be expected in the normal and healthy at rest, an exercise-driven TSH under the most stressful conditions may be unlikely to go much above 3.0 in a healthy individual.

The chemistry of muscle damage and its relationship to hypothyroidism

If physical activity brings up TSH levels, muscle damage should also be evident. The enzyme creatine kinase is recognized as a by-product of muscle damage. Troponin is another enzyme which is elevated specifically in cases of heart damage; above certain levels, it is considered diagnostic of heart attacks. Hekimsoy and Oktem (2005) concluded that creatine kinase levels were abnormally high in 57% of patients with "overt hypothyroidism" and in 10% of those with "subclinical hypothyroidism." Unfortunately, they did not give their particular criteria for diagnoses of the thyroid conditions in the abstract.

On the other hand, Ness-Abramof et al. (2009) determined that none in a sample of 25 patients with very high TSH levels (30-75 mIU/L) had abnormal troponin levels. Again, because only the abstract was available, it was not clear that this simply meant they were not diagnosed with heart attacks. On the other hand, 14 out of these had abnormally high creatine kinase levels, with a range of 86-1221 "U/L," where 170 U/L was considered to be abnormally high for women and 195 U/L for men.

So this raises these questions: 1) Are hypothyroid people experiencing the same type of muscle damage as those who overexercise? and 2) will overexercise present (itself) in the doctor's office as hypothyroidism?

Iodine in other parts of the body: how their needs impact thyroid function

Anything involving iodine has to be related to the thyroid, so studies of its effect on other parts of the body have to be considered.  Eskin et al. (1995) have come to the conclusion that precancerous and cancerous breast tissue take up iodine, which may trigger apoptosis in that tissue.  In previous studies, they had determined that thyroid hormone had no part in this process.  However, this could have an impact on thyroid function if the iodine that would have otherwise been incorporated into thyroid hormones were taken up by sick breast tissue (or an overactive thyroid might hog the iodine).  Stoddard II et al. (2008) did an in-vitro study of the effects of a combination of ionic iodine, i.e., in potassium iodide (KI), and molecular iodine (I2) on  a line of estrogen-responsive breast cancer cells derived from a woman, i.e., from the MCF-7 cell line.  They used microarray analysis, a method to measure gene expression, to determine the probable tissue changes in these cells, and discovered three genes that up-regulated steroid metabolism (which I think means breakdown of steroids, which include the estrogens) and three genes down-regulating estradiol production.

Neglected areas of study and other factors

The infection connection: can early infections lay the groundwork for autoimmune hypothyroidism, and are hypothyroidism patients more susceptible to, say, low-grade viral infections?

Previous research has strongly suggested that illness, especially critical illness, might overburden the thyroid by the demands it places on it. But what about the possibility that collaterial damage to the thyroid, perhaps permanent, might be inflicted by the action of the immune system as it fights infections that attack other parts of the body? Is it possible that the severe febrile illnesses that we used to call the "childhood illnesses," for instance, attack the thyroid or confuse the immune system in ways that cause it to develop anti-thyroid antibodies? Could these conditions be the major causes of Hashimoto's thyroiditis?

Menopause (and adolescence)

There is one great research gap: the study of menopause as timing for the onset of hypothyroidism.  Although menopause is not a disease, it is a time when disease risk increases, maybe because the great change in hormone levels makes homeostasis, that state of ideal physiological balance necessary for health, more difficult to achieve.  As we learned in biology class, long-term upsetting of homeostasis can lead to a great variety of diseases.  Adolescence is another time of life that challenges homeostasis, as higher teenage male TSH levels seem to suggest.

It seems to be popularly believed that any simply apparent, simultaneous occurrence of menopause and hypothyroidism in an individual can be explained by the similarity of symptoms.  A simple online search can turn up articles promoting this point of view from a variety of sources which suggest that the signs and symptoms of menopause are routinely mistaken for those of hypothyroidism and vice versa. 

Lack of personal relevance to physicians

Very few physicians have personally experienced hypothyroidism or menopause.  Because they have entered the field relatively recently, most women physicians are too young to have experienced menopause, while the extremely high energy demands made on medical students, interns, and residents effectively screens out those with vulnerable thyroids.

Inability of affected individuals to advocate for themselves (and misleading signs of recovery in those who are treated))

Is it possible that many, if not most, patients with even "subclinical" hypothyroidism are too ill to find their way to physicians or to speak out publicly on the general issue of hypothyroidism?  Have they learned to be passive and trusting in order to conserve their energy?  The flip side of this problem is that when hypothyroid individuals receive treatment for their disease, they might become more assertive and set higher standards for their well-being, which might be misinterpreted by their physicians to be a sign of worsening health.

Social attitudes about the signs and symptoms of hypothyroidism

Hypothyroidism tends to make its victims sickly and unattractive, and perhaps prone to complicating diseases which in themselves carry severe social stigmas. These attitudes, sometimes shared by physicians, might keep sufferers from getting the help that they need.

Cultural differences affecting government oversight

The United States and western Europe have fundamentally different missions in healthcare, which necessarily affects their approach to the prevention and treatment of thyroid disease.  The US places its highest emphasis on longevity, and therefore focuses on the diagnosis, treatment, prevention of (and screening for) the diseases that are the most frequent immediate causes of death, such as ischemic heart disease, diabetes, and cancer, and only secondarily on those diseases that cause significant pain and disability without being fatal in the short run, even though they might set the stage for the killer diseases.  On the other hand, the Switzerland-based World Health Organization is apparently more concerned about the ability of citizens to function normally in society, to be free of unnecessary handicaps, both mental and physical ones, in essence, quality of life; it has apparently set the bar higher in recent times as public health has improved.  The concept of quality-adjusted life years (QALY) is a European one.

Economic factors

Hypothyroidism is hardly a cash cow for the medical care industry.  Patients who receive standard treatment, i.e., one T4 pill a day, generally pay $25 or less a month for this (although drug prices in general have shot up in late 2016) and see a doctor to get a prescription once a year, typically at the annual physical, where they are tested only for TSH levels specifically in connection with this disease. On the other hand, treating hypothyroidism's individual signs and symptoms separately is more lucrative: statins (and their successors, PCSK9 inhibitors) and antidepressants can be very expensive.  Figure in the estrogens and progestins that many women are prescribed at menopause, often to treat psychological pain, and this is quite a bit of money!

Another factor is the cost of diagnosed disability: a condition that is diagnosed mainly on the basis of symptoms is likely to draw suspicion of attempted fraud on the part of patients who report them because certified disability can bring such a patient financial benefits. Therefore, even if a standard treatment exists for such a condition, a physician's concern about protecting the financial interests of the patient's employer, the government, or of the involved insurance company, might override that physician's feelings of obligation to meet the patient's health needs.

Conflict of interest on the part of the patient: real or imagined

Do physicians typically suspect patients claiming to have hypothyroidism symptoms of having ulterior motives, such a wish for diet pills or for a respectable alternative to a psychiatric diagnosis? Are they suspicious of patients who are open about wanting to avoid taking statins? How often do physicians suspect sufferers of lying about substance abuse?  Is it possible that so many people in a particular region have wanted to see thyroid specialists in the past for problems that turned out to be unrelated to thyroid disease that new patients are routinely turned away or discouraged by requests for mountains of paperwork up front?   What can be done for those with thyroid disease facing this regional medical care problem?  Is a local thyroid specialist shortage a factor in raising the upper limit of the TSH normal range locally?  As the opioid abuse epidemic moves into the spotlight and the proportion of physicians who have grown up in high-crime neighborhoods increases, will patients feel increasing pressure to prove that they are not selling levothyroxine on the black market?  Patients who live in blighted neighborhoods or in cities with high poverty and crime rates might find it especially difficult to convince physicians that their reports of symptoms, now necessary for diagnosis according to the new guidelines, are sincere.


Questionable Science

The concept of "subclinical" hypothyroidism as a subset of hypothyroidism that does not really need treatment and in fact has no real effect on the quality of life of those deemed to have it is built on very shaky foundations, although this problem is apparently easy to overlook.  Somehow, within just a few years, decades, even centuries, of insightful and skillful research characterized in part by development of very sophisticated technology (and great, if imperfect, consensus among physicians), what was considered to be settled science has been mostly overturned for these patients, who are now in danger of being deprived of care based on the results of several deceptively designed experiments and on a new emphasis on clinical trials.  In the past, ethical and financial considerations limited clinical trials to the examination of the aspects of medical care, e.g., new drugs, associated with unknown and possibly great risk because of the absence of information about their effects.  However, a 180-degree turnabout in medical care policy is occurring as our government conducts an overhaul of professional medical practice, emphasizing the results of randomized clinical trials and (intrinsically difficult-to-validate) meta-analyses in its judgments of which forms of medical care to discard from standard practice. This has meant in some cases that those treatments which had occasioned the fewest clinical trials on the basis of ethical considerations because of their generally accepted safety, efficacy, simplicity, and low cost became unavailable to patients who had relied on them to maintain their health.  Perhaps worst of all, in a sharp deviation from tradition, such science is apparently "settled" by our government without the possibility of appeal.

Dependence on a few recent studies that use samples not representative of the relevant population

The formally stated definition of "subclinical" hypothyroidism is based entirely by TSH and thyroid hormone levels, i.e., that the former is abnormally high but the latter are normal.  However, subjects in studies of this condition had one more important characteristic: they were not currently being treated for hypothyroidism at the start of the study, therefore they do not properly represent the entire population of individuals who would have had these hormone levels without treatment.  How many people now being treated for hypothyroidism had these "subclinical" levels before being treated?  Suppose their numbers are much greater than their counterparts who are not being treated?  Is it obvious, then, to recommend withholding treatment from all individuals with "subclinical" hormone levels, regardless of the reason that they are not currently receiving treatment?   How many will lose the treatment they are currently getting on the basis of the new standards?

How much "overt" hypothyroidism is complicated hypothyroidism?

What proportion of those diagnosed with "overt" hypothyroidism, i.e., those with elevated TSH levels and low T3 and T4 levels, have a non-thyroid illness in addition?  This has apparently not been studied specifically, but previous studies regarding the effects of critical illness suggest that this is an issue worth examining.  It stands to reason that a serious illness such as cancer or diabetes would put extra stress on the thyroid, and could pull thyroid hormone production down below the normal range, especially in individuals who already were in the "subclinical" range.

We know that the pituitary gland compensates for the decreasing productivity of failing thyroid follicles by stimulating the production of new thyroid follicles, which at high enough levels produces a visible goiter.  If enough such follicles are produced, together they can create enough T4 (and a little T3) to keep total thyroid hormone levels in the normal range.   But this is not the same as having normal thyroid function.   No one claims that overt hypothyroidism does not product more severe symptoms than subclinical hypothyroidism does; however, the question is whether patients should have to become frankly ill, perhaps to the point of experiencing irreversible damage to their health, before they can receive T4 replacement therapy.

Circular reasoning: should psychological measures be used to validate TSH level normal ranges used for treatment purposes and vice versa?

The recent meta-analysis used psychological measures to support the claim that "subclinical" hypothyroidism is not characterized by a worsening of quality of life.  Yet endocrinologists disagree, arguing that psychological measures are not a reliable measure of the severity of thyroid disease because they are not unique to the disease.  This implies that it would be difficult, if not impossible, for someone with "subclinical" test results to persuade a physician that s/he needs treatment on the basis of symptoms.  And the one validation study that turned up, one of the Billewicz Diagnostic Index, used psychological well-being as the dependent variables and TSH and thyroid hormone measurements as independent variables, the reverse of what the Feller et al. meta-analysis did.  

Hypothyroidism might cause fatty liver disease, but U.S. researchers have have focused on the more tenuous apparent relationship to heart disease

Meanwhile, as U.S. researchers cast about for ways of justifying cutbacks in "subclinical" hypothyroidism treatment, those in other countries, such as China, France, Italy, Mexico, and Iran, have found evidence that even mild hypothyroidism can harm liver function, increasing fat deposition in the liver and raising blood triglyceride levels because of the functions that TSH and thyroid hormone receptors in liver tissue have.  Since the health of the liver quite likely has an effect on the heart, thyroid health probably, however indirectly, affects heart health.  But the justifying studies might still need to be done, since there has been very little interest in that area.

Problems with pedantic interpretations of p-values and of odds ratios are complicating interpretation of relevant studies

The problems with the underpinning science are evident in heaps of seemingly innocuous detail.  For example, interpretations of p-values and odds ratios appropriate (i.e., extremely small and large, respectively) to the efficacy sections of clinical trials of new drugs have been applied to what are essentially safety studies; for instance, what happens to hypothyroidism treatment standards when a strong but imperfect relationship between TSH and triglyceride levels is dismissed as nonexistent in a study that busy government bureaucrats assume is sound? In recent years, some recently published case studies have reflected a sharply changed approach to diagnosis and treatment of "subclinical" hypothyroidism.  There seems to be a new attitude, reflected in recently published case studies, that "subclinical" hypothyroidism is a temporary condition that often can be cured by a few months of levothyroxine treatment, and that TSH values below the arbitrarily set value of 10.00 do not represent a health problem; yet apparently no studies involving multiple patients support this point of view. 

Setting down hard-and-fast treatment rulings based on sparse information

American professional endocrinologists' associations have thus far dismissed measurement of clinical signs and symptoms as impossible, perhaps because of their reliance on observational studies classifying subjects by implied diagnosis at the start; the U.S. Preventive Services Task Force disagrees, citing an U.K. clinical trial studying the effect of T4 treatment on the incidence of ischemic heart disease and suggesting that a similar trial be done relating "subclinical" hypothyroidism in previously untreated subjects' quality of life to T4 treatment. Although this is a valid criticism that has the potential to lead to a professional consensus about the diagnosis and treatment of hypothyroidism, the "I" statement, a refusal to offer an official recommendation, might leave "subclinical" hypothyroid patients in an indefinitely prolonged state of treatment limbo.

Each side misunderstands the other in an important way: the USPSTF seems to lack a full appreciation for the moving target which endocrinologists have been trying to hit over the years, with the dramatic improvements in the precision of TSH assays from the 1950s through about 1990 brought about by clinical biochemists. On the other hand, American endocrinologists have relied too much on observational studies with "dry" independent variables and oversimplified definitions (with arbitrary, somewhat varying, TSH measurement bounds) of "subclinical" hypothyroidism which contribute little to pinning down the limits of a truly workable normal range; they have also relied heavily on their own experience in treating individual patients. A randomized, double-blind clinical trial, on the other hand, would allow physicians to examine subjects and to include their professional judgment of the severity of such a subject's signs and symptoms as a key endpoint in these trials without bias being a problem. However, such a trial is difficult to do when the main instrument used to measure hormone levels is still undergoing improvements, and will have a delayed effect if it takes place over several years.

How will various physicians, group practices and medical centers react to this task force's "I" statement before the recommended clinical trials take place?  Will they see it as a wake-up call, or as a license to take liberties with diagnosis, refusing treatment to patients who are not seriously ill?  Although the USPSTF has repeatedly insisted it is merely an advisory organization which does not consider financial factors in its recommendations, lawyers serving the medical care industry might interpret its findings quite differently. This is hypothyroid patients' major and most urgent dilemma today: they have fallen through the cracks because government, legal and financial considerations have superceded the professional concerns of health care providers and of clinical biochemists.

Yet many important questions remain unanswered.  Will factors other than TSH levels, such as medical and family history, be involved in diagnosis?  Are there concrete, measurable signs of disease or deficiency that can be pinned to certain TSH levels?  What about anti-thyroid antibodies and iodine levels? At what levels can we tell that disease-free individuals are exercising too much or are simply too sleepy to function normally?  But, more important than ever, how can we ensure that medical care for those with hypothyroidism will not worsen or become less available while official standards are being pinned down, until the endocrinology field and the USPSTF come to an agreement? The message to physicians at this point seems to be: let your conscience be your guide.  Instead of hoping for perfection in pinning down the ideal normal/abnormal cutpoint at each end of the normal range, why not let physicians use their increasing wisdom about TSH levels and their relationship to patient distress to perform their job well, if not perfectly according to official criteria? What legal protections can we offer patients whose thyroid function is compromised, but not dramatically so?

Problems with relying on TSH levels alone for diagnosis

Mechanisms: what we know about how TSH works

The medical establishment justifies its emphasis on TSH levels as the main criterion for hypothyroidism diagnosis by claiming that it is the most trustworthy measurement of the severity of the disease. In an important sense, they are right: TSH assays have become extremely precise in recent years (although it appears that some products are better than others), and studies of the effect of exercise intensity and circadian rhythms have shown a close correlation of TSH levels, melatonin levels and feelings of alertness. We also know that TSH levels and goiter growth are strongly related, and that at least some viral infections can drive up TSH production by the intestines as well as causing atherosclerotic changes. Knowledge of these mechanisms should make us wary of conclusions drawn from clinical research that claim that an abnormally high TSH is not really a problem in itself. But apparently knowledge of this relationship between TSH and certain psychological states and physical conditions is used to justify using TSH levels in lieu of subjective judgments of the patient's degree of impairment: this is useful only to the extent that an "abnormal" TSH level can be pinpointed: what reference should be used?

Can we really measure the precision of normal range limits?

On the other hand, this knowledge cannot serve as a basis for very precise measurements of the limits of the TSH normal range; in fact, it is not clear how to determine the precision of this measurement at all (at least given that membership in the "healthy patient population" requires subjective judgments). Yet these limits are typically reported using two significant figures, e.g., 4.5 mIU/L for the top of the normal range. In practice, however, a lab test result reported as "4.4" mIU/L (even though greater precision, represented by more significant figures, might be possible) would be probably be interpreted by many physicians to be "normal." How big a fudge factor is necessary in reality? And how should clinical signs and symptoms figure into that? Maybe it's not necessary to find the magic number: if a patient's TSH level is close to the top of the normal range, perhaps it is reasonable to consider treatment, and perhaps rather inhumane to dismiss the possibility out of fear of deviating from perfection.

To add to the confusion: changing precision of TSH assays, resulting in two normal ranges?

There seem to be two normal ranges in effect in the USA: one based on modern assays with minimal error, with an upper limit ranging from 4.0 to 5.5 mIU/L (depending on the particular lab), and another, apparently based on old, imprecise assays, with an upper limit of 10 mIU/L (today treated effectively as 10.00 mIU/L).  Because this old assay imprecision kept it from being feasible to determine the bottom of the normal range, the earlier approach to treatment was apparently to lower the TSH of diagnosed patients to just a little below 10, thereby minimizing the risk of going below what would have been the bottom of the normal range had they been able to measure it.

The dramatically increasing improvement TSH level assays, from a 5-10 mIU/L error in 1965 to one of 0.01 mIU/L in about 1989, might have introduced some confusion in itself.  While physicians who have completed their training after 1989 might be comfortable with a normal range upper limit of, say, 4.5 mIU/L and the implication that higher values might indicate disease, those who completed theirs at a date closer to 1965 might be more comfortable with rounder numbers, such as 10 mIU/L for such an upper limit. Could it be that these older physicians might dominate the power structure of the profession and therefore might be responsible for the rule discouraging T4 supplementation therapy for patients whose TSH is below 10.00 mIU/L (in practice)? Yet, according to standard significant figures rules, "10" actually represents with certainty any number between exactly 5 and exactly 15!

Representative of this point of view is the caution that the AACE insists on exercising in the treatment of patients whose TSH test results are between 4.12 mIU/L (or the upper limit of the normal range of their local lab if it is available) and 10.00 mIU/L (effectively). Is it possible that 4.12 and 10 are really just new and old measurements of the same value, and used without awareness of their real meaning?  Is there much of a scientific basis for awarding them equal significance? And isn't it interesting that, as TSH assay precision improves, the top of the "reference range" keeps going down in most labs?

Fear of triggering hyperthyroidism

Fear of inducing hyperthyroidism evidently causes physicians to be very reluctant to diagnose hypothyroidism; patients with abnormally low TSH are much more likely to be diagnosed with thyroid disease than those with high TSH.  However, of all the causes of low TSH, Graves' disease is by far the most dangerous to health and the most difficult to treat, and apparently fear of the other causes might be exaggerated because of their association with it.  The CDC picked up on this bias in a study, and some Cleveland Clinic physicians were moved to write an essay addressing this overreaction.

Clinical research issues: some crucial data might not be available because of ethical rules

Much clinical research regarding the association between SCH and blood lipid levels has been done. One concern I have is about handling subjects taking lipid-lowering medication; if they are included in studies, there is no ethical way to compensate for the missing information about what their lipid levels would have been without treatment, while if they are excluded, this may bias the study by eliminating subjects whose blood lipids were most heavily influenced by hypothyroidism. This, of course, is similar to the problem of including only subjects with SCH not being currently treated: they may be unusually healthy in other respects.

There is some evidence of a causal link between subclinical hypothyroidism and "bad" blood lipids. Here more research should be pursued: untreated people with SCH might be more likely catch infections, perhaps because of their cold intolerance, and acute infections might worsen their blood lipid levels, even months after they recover from them.

Screening for thyroid disease: a lingering controversy and maybe a downward spiral

A strange thing has happened to the screening process for thyroid disease. Although five professional physicians' groups recommend screening and provide screening guidelines, their input is apparently trumped by that of the U.S. Preventive Services Task Force, a group of internists which is currently undecided about whether to recommend screening for thyroid disease, most recently because of its concerns about the need for new clinical trials evaluating the relationship of T4 treatment to symptoms. Although the USPSTF's concerns are valid, patients may suffer in the short term from the resulting vacuum in formal treatment standards. Not only are more diagnoses likely to be missed and fewer new patients treated in the short term, but a downward spiral is likely to result: physicians may become more likely to lose touch with the incidence and manifestations of hypothyroidism, leading to increasing errors in the identification of the "healthy patient population" and therefore in the diagnosis of the disease.

Is this is a classic case of disagreement about the chances that differing approaches might cause harm?  Has the USPSTF decided that the most dangerous mistake was a Type I error, i.e., a false positive in diagnosis?  Have the physicians' professional groups expressed in their recommendations that the false negative, the Type II error, posed a greater risk to patient health?  Is this the sum of it?

The difference is actually more fundamental.  The USPSTF's 2015 paper is actually a request for endocrinology researchers to clean up their act; it is best read as a protest against fundamental problems with the endocrinology establishment's approach to diagnosing thyroid disease.  It brings up many of the points already made in this essay, e.g., the continuous frequency distribution of TSH and thyroid hormone values, described as a "spectrum" and a "continuum," rendering the quest for precise upper and lower normal range limits based on mainly mathematical considerations absurd; existing differences in professional opinion about more recent limits weaken their validity.  It states that, in order for the TSH normal range to be meaningful, there need to be studies to pin down the "association of TSH level with symptoms, adverse outcomes, or particular risk factors for disease." The USPSTF paper found only one paper, a retrospective observational study that found lowered risk of "ischemic heart disease events and overall mortality" in subjects with "subclinical hypothyroidism" (Razvi et al., 2012) and no studies of the effects of treatment of "overt" thyroid disease on any non-thyroid diseases. However, it does not question the arbitrary upper limit cutpoint of 10 mI/L, which it claims to be the only value which endocrinology researchers could agree on. However, this is not really true: although there are some differences of opinion among researchers, most seem to believe that the top of the TSH normal range should not be above 4.5 mIU/L, although practitioners in general also seem to feel reluctant to insist on treating patients with no complaints in spite of having TSH values at that level and at some higher than that.

Acute non-thyroid disease in "borderline" or "mild" hypothyroidism

Some patients manage to keep their TSH within the normal range while they do not have any other medical problems, but infections might send their TSH values up, making it harder for them to recover. Other patients who have been diagnosed with hypothyroidism might need an increased dose of T4 when they develop febrile illnesses. Although a great deal of research has been done on patients with "critical" illness, and there is recognition that a rise in TSH is an early finding in non-thyroid illness, there does not seem to be a plan in place for patients whose thyroids are not up to handling the extra stress of the "flu" or of other common but serious illnesses.

Stimulants (chemicals raising dopamine levels), exercise and how they complicate hypothyroidism diagnosis

The picture is complex, but the pieces are coming together: A "normal" adult daytime blood TSH is a little less than 1.5 mIU/L, but this rises to about 3.0 at midnight in someone who stays up that late and falls gradually back down to the former value sometime in the morning. Vigorous exercise at night can double that value. TSH values have been shown to lead melatonin values by a short time interval; otherwise the two curves have practically the same shape; therefore TSH levels are reliable predictors of sleepiness. This also suggests that raising TSH levels might increase sleepiness.

But there is a way that people who want to sleep less and exercise more can get around this: stimulants can lower their TSH, reducing or eliminating their sleepiness. Unfortunately, this means that hypothyroid people who self-medicate with stimulants to get through the day or even to support an athletic regimen might not be diagnosed, even if they manage to get tested. But they are unlikely to get tested, because 1) TSH levels are not among the standard screening tests for people of any age and 2) these hypothyroid sufferers dependent on stimulants are more likely to perceive their problem as one of addiction, not endocrine in origin. And if they come in for testing, their TSH levels might be artificially lowered because of the dopamine intake, sometimes from above the normal range upper limit to somewhere within it.

But the plot thickens: taking in stimulants is not the only way to raise dopamine levels in the brain: exercise does it too (Sutoo & Akiyama, 2003). Now consider people who take in stimulants to boost their energy levels to increase their exercise or athletic performance, and it stands to reason that their TSH levels will go down, maybe a great deal. They will sleep less and, at least for a while, feel good. They probably will not tell their physicians that they suspect hypothyroidism and will not get tested for it as a result. Down the road, they are likely to wind up in that "normal" patient population that laboratories use to determine their normal ranges because, as so many health-conscious people do, they get annual physicals.  When they come for these physicals, typically early in the day, they typically have been fasting for at least 12 hours. Therefore, they are unlikely to be experiencing the TSH-lowering effects of stimulants (or exercise, for that matter). Their TSH levels may go very high as a result, possibly raising the upper limit of the TSH "reference range." Another factor that can drive up the TSH of health-conscious patients is their greater tendency to avoid table salt and therefore to take in less iodine.

And maybe there's another consideration. In the kind of health-conscious areas that produce these vigorous exercisers, labs are likely to use better techniques, which are more likely to lower the measured TSH for individual patients, since "Technical problems, especially with the washing step, may result in falsely high TSH values" (Demers and Spencer, 2002). As improved techniques bring down these measurements in such an area, could the change in reference range limits can lag behind because of the great variation in the old and new data combined to develop these limits?

Of course, exercise makes the thyroid work harder. How much exercise, both in terms of intensity and duration, is too stressful? Could too much do permanent damage to the thyroid and how much would that be? I was not able to find any relevant research.

Are women really more likely to get hypothyroidism more than men are? What about (overlooked) racial differences?

We now know that estradiol, which increases in blood concentration by a factor of about 200 during pregnancy, reduces the proportion of iodine available to the thyroid because it routes some of that iodine to the breasts and to the placenta. Although a healthy thyroid can increase its output to maintain T4 and T3 levels, hypothyroid women experience a rise in TSH in order to accomplish this, sometimes above the upper limit of the normal range; as a result, they need to have their supplemental T4 dose adjusted upwards. 

This raises a puzzling question: the sex difference in estradiol levels is much less in the case of women who are not pregnant. Would these women be so much more likely to become hypothyroid than men, given this small difference? Could it be that just one pregnancy (which most women experience) is enough to cause long-term thyroid problems, and that therefore the typical woman presented in statistics is one with a pregnancy-damaged thyroid? Another factor is the use of supplemental estrogen in the form of birth-control pills or hormone replacement therapy, which many women use. But what about the woman who neither gets pregnant nor uses pills containing estrogen(s)? Is she any more likely to get hypothyroidism than the typical man?

Why is the much bigger interracial incidence difference ignored? Why do "Black, non-Hispanic" Americans have lower TSH levels (and lower rates of hypothyroidism) and higher urine iodine levels than their "White, non-Hispanic" counterparts? What does this suggest about the influence of iodine intake on TSH levels? This area is ripe for research.

Concomitant illness and its confusing effect on TSH and thyroid hormone levels

I would like to see more studies of how acute illness, e.g., influenza, bacterial bronchitis, and other common but stressful diseases affect those with TSH levels in the "subclinical" range, and whether such illnesses drive up TSH in those whose daytime TSH is typically well above average but not outside the normal range. Are there borderline cases out there that function normally when free of non-thyroid diseases but who get especially severe cases of influenza and readily develop complications from it? And do these affect blood lipids? Promising research indicating production of TSH by the intestines in case of viral infection and that these infections cause atherosclerotic changes indicates that diagnosing and treating minor (and perhaps chronic and low-grade) viral infections may not only lower elevated TSH but reduce the chance of those afflicted developing heart disease. Furthermore, would giving supplemental T4 to flu sufferers whose typical TSH values are borderline high ease the severity of their disease and take some of the burden off their hearts?

I am going out on a limb here: existing data seem to suggest that a TSH high enough to go past the upper limit of the conventional American normal range (5.5 to 6.0 mIU/L) is likely to be caused by (usually undiagnosed) concomitant non-thyroid disease. Overexercise, lack of sleep and various other conditions in normal life can drive a daytime TSH up to 3.0 or 4.0, but to me the far limit of "normal" is a red flag. And what about patients with difficult-to-treat non-thyroid diseases that are putting stress on the thyroid? In the early stages of such diseases, when the TSH rises out of the normal range, such patients will be given supplemental T4 according to current American standards, which I think is good. The controversy seems to come in when these diseases progress, bringing the TSH back down into the normal range, bringing patient T4 levels down with it, especially when the latter go below the normal range. It seems that a disease with that level of severity would be giving the thyroid more stress than it should be handling and that some of such patients might benefit from supplemental thyroid hormones. I know of no researcher who has considered supplemental T4 for such people, although one researcher has considered using related pituitary hormones with growth hormone for critically ill patients. However, some researchers have discovered that all HPT axis hormones can also be "reset" to normal values (with a slight decrease over time) in critically ill patients via TRH and GHRH infusions without adversely influencing their survival, a step in the right direction.

But what about the patient with "euthyroid sick syndrome," i.e., with a TSH in the normal range and a low T4? According to Merck (2006, p. 1194), these people should not receive any HPT axis hormone supplementation, simply treatment for the concomitant illness, even it is serious, chronic or even progressive. What about patients with symptomatic cancer or diabetes? Do we know whether these diseases put enough strain on the thyroid for supplementation to be beneficial, if not necessary for recovery?

The (Alzheimer's ?) dementia connection

A patient who had suffered from severe hypothyroidism and whose mother was diagnosed with untreatable dementia tells a chilling story that strongly suggests that the latter fell through the cracks of a medical care system that failed to consider hypothyroidism as a possible cause of her dementia and extreme physical decline (Shomon, 2000, 57-62). Although in theory patients suspected of having Alzheimer's are screened for hypothyroidism, it would seem that an excessive emphasis on narrowly defined normal ranges for certain lab tests could cause patients to be wrongly diagnosed with irreversible dementia, given inappropriate medication, and eventually confined to nursing homes. 

Recent research has associated a genetic defect hampering the T4-to-T3 conversion with genetically linked progressive neurological disorders.  This suggests that hypothyroidism in general may have an adverse neurological (as well as psychological) effect, and that it may in fact cause such disorders.  However, this discovery should not have been necessary for patients with this problem to be correctly diagnosed and given appropriate treatment: their blood tests should show an abnormally low T3-to-T4 ratio, and T3 drugs have been available for a long time.  This does not seem to have a relationship to the genes implicated in Alzheimer's; however, its characteristic neurological symptoms and signs might cause advanced untreated hypothyroidism (which in some cases may be overlooked because it may be accompanied by normal TSH and T4 levels as these recent studies demonstrate) to be ruled out as a cause and to be diagnosed as Alzheimer's instead.

Iodine supplementation: how much is needed and the problems associated with determining that

There might still be iodine deficiency in the U.S., and it might have some simple factors: since potassium iodide may have a tendency to fall to the bottom of salt containers because it is heavier than the salt to which it is added in the iodization process, simply shaking up salt containers before use may make a big difference in an individual's iodine intake! But we really do not know, because the rigid distinction our healthcare system makes between nutrients and drugs makes this whole issue fall through the cracks.  According to the official numbers, the United States has the smallest proportion of citizens showing signs of iodine deficiency, but are those gathering statistics here working as hard and making the right assumptions as those in other countries?

The iodine issue needs to be revisited. It seems to be widely accepted that TSH levels say all that needs to be said about iodine deficiency and that it is best just to treat any case of hypothyroidism with T4 supplements, but this means that an overlooked case of iodine deficiency could lead to a lot of unnecessary doctor visits, at the very least. And it is probably easy to overlook iodine deficiency because it is hard for an individual to tell whether s/he is getting the right amount, although the information on iodized salt packaging is very helpful. The amount of iodine in food and water varies a great deal by geographic location in the U.S.; we knew that almost 100 years ago. And I have not been able to find any statistics on current regional iodine intake. Besides, even though it makes sense to use iodized salt, not everyone is doing it, although some are getting 150 mcg per multivitamin pill. Since we tend to be reminded so much about certain medical issues, I suspect that many people believe that the government would nag us to use it instead of discouraging us from using salt of any kind if it really mattered. In any case, however, it is important to remember that we Americans are on our own in general when it comes to nutrition.

I still feel in the dark about the deadly thyrotoxicosis that struck some people at the outset of salt iodization, not just in the U.S. but in Tasmania, Europe, South America and central Africa. Thyroid nodules still exist, yet the thyrotoxicosis problems occurred only at that particular time. Could it be that there were early problems in the salt iodization process that were quickly cleared up? If this had been the case, perhaps the WHO's "optimal" daily iodine intake amount has been set too low, too cautiously. At any rate, such a program might have been handled differently today, depending on whether iodine were classified as a "food" rather than a "drug:" the FDA might have provided oversight of the manufacturing process and run clinical trials on a limited number of carefully supervised subjects, trying different doses. Maybe the data on the process by which the WHO decided on its categories are available, but hunting them down is too big an undertaking for this essay. The data from the Food and Nutrition Institute, which concluded that 1.1 mg a day was the upper limit on safe iodine intake, suggests that recommended iodine doses might be too conservative.

What is missing altogether is the application of much of this knowledge to the individual patient.  Women approaching menopause, adolescents, and people whose thyroids are overwhelmed only when they have the "flu" or a similar acute illness are especially neglected by existing research. These cases, of course, are part of a larger picture of special stresses on the thyroid being caused by challenges to homeostasis, that normal metabolic balance that keeps us healthy.

Ideal patient education: the easy and the hard parts

It is vitally important to educate patients about the treacherous nature of hypothyroidism, both with respect to diagnosis and treatment. At the very least, they should be warned that taking dopamine agonists (better known as "stimulants") may bring down their TSH and T4 levels in the short term, potentially causing false negative results on relevant hormone tests.  It makes sense that many with untreated or undertreated hypothyroidism would be motivated to self-medicate with caffeine and nicotine; they need to understand why taking in stimulants might create special problems for them, masking and aggravating their condition at the same time.

Educating patients about thyroid-specific nutrition may be less helpful, especially with regard to iodine.  People in most age groups get most of their iodine from dairy and grain products, but they have no way of knowing whether they are getting the right levels in their food.  Perhaps their best indicator is their geographical region: the further north (in the U.S., anyway) they are, and (to a lesser degree) the farther they are away from the Gulf of Mexico and the Atlantic and Pacific Oceans, the less iodine is likely to be found in their food and water. But it seems that a physician cannot provide much individualized help in this crucial nutritional matter since individual iodine level screening is not part of standard medical practice.  Finally, patients should get advice on how to use iodized salt without getting too much sodium overall.

Another thing to consider: why not teach patients how to examine their thyroids? I dispute a commonly held belief that a person's thyroid cannot get smaller over time. This could also be a good starting point for research about this clinical aspect of thyroid health and function.

Individuals also need adequate levels not just of iodine but of tyrosine, a building block for thyroglobulin and many other related molecules, and selenium, a building block for the D1 deiodinase.

"Normal" range issues: TSH, continuous value variables and precision

It is important to remember that "reference ranges"/"normal ranges" are human creations, not discovered facts of nature. There is a lot of subjectivity going into their establishment and cultural attitudes seem to figure very heavily into this. I'd like to see this studied: are these ranges wider in countries where there is a more adversarial relationship between physicians and patients?

There is something inherently absurd about trying to find a hard-and-fast cut-off value on a smooth distribution curve of a continuous variable because the two values on either side of the cut-off point are most likely to be extremely similar. In essence, standard normal range determination assumes that measurement error of these cutpoints is negligible when in fact there does not seem to be an existing method for determining that error.  This is one reason why there is so much disagreement in the field about this.  Although it does not seem clear how to measure the precision of these determinations, the limits of normal ranges for these types of variables typically contain two significant figures.

The spectrum nature of hormone values does not have to be a stumbling block to treatment. One approach to this problem already in effect is to make available many different dose levels of T4 and to put a patient with marginal hypothyroidism on a very small dose. Abbott Labs (2013) Synthroid has 12 such levels, ranging from 25 to 300 mcg.

On one hand, it seems that the finest assays available have negligible measurement error.  However, can we determine the measurement error in the calculation of the normal range limits of a continuous variable?  How many significant figures should these normal range limits have?  It seems that the science on which these are based is rather murky. Therefore, it is unreasonable to define these limits with extreme precision; physicians should be allowed some leeway in making their determinations.

Menopause: a neglected factor

The biggest gap that I see in thyroid function research is that regarding the impact of menopause on thyroid disease and on health in general. I would like to see the medical establishment start to recognize that 1) menopause is not a disease and yet 2) because the unstable hormone levels during "the change" challenge homeostasis, the risk of disease in general increases as a result. I notice from general reading, even from ads from medical practices, that there are a lot of people who have noticed that hypothyroidism tends to strike during this time. Yet I was not able to find any research articles on this subject.

Determining threshold levels, in general: the devil in the details

At what level does iodine deficiency aggravate the effects of certain environmental pollutants? What exercise level is too stressful for the thyroid? How to adjust for assay differences, especially those caused by heterogeneous forms of TSH or forms of hCG extremely similar to some forms of TSH? So often known issues are neglected because the authorities do not have the specific numbers they feel they need to draw the line.

What's the story on "evidence-based medicine?" Who decides what it is?

The priorities guiding the application of evidence-based medicine vary greatly by country and culture, whether it is longevity, quality of life, the occurrence and/or timing of certain adverse events, or the results of certain laboratory tests or types of diagnostic imaging.  It appears that hypothyroid patients are more likely to be treated where quality of life is considered to be the main factor, and less likely where the focus is on longevity and the tendency to associate "bad" results on certain tests, most notably blood lipid tests, with an irresponsible lifestyle and a rebellious attitude toward medical authority.

Evidence-based medicine is only as good as the science on which it is based, and on how well and thoroughly it is applied to patient care. Where a part of this body of knowledge is absent or sparsely represented, this makes physicians' decisions about patient treatment more difficult if they are required to follow rigid diagnostic and treatment standards based on that knowledge vacuum created by conclusions drawn by this poverty of information, or so implied in a legal light.   Given past reluctance to perform clinical trials testing well-accepted treatments because of concerns about harming subjects, this could lead to conclusions based on dangerous misunderstandings about these treatments.  When faced with this situation, physicians might often lean toward Type II errors and refrain from treating a patient who is not acutely ill. The sea changes caused by the bureaucratization of medicine are causing physician burn-out at ever higher rates; as one disillusioned physician put it: "I feel like a pawn in a moneymaking game for hospital administrators" (Jauhar, 2014). Are these standards really set by a single task force? And who decides what a large body of relevant research articles implies about diagnosis and treatment?

The perfect is the enemy of the good: what about patients' needs?

Should not the ultimate criterion for quality of healthcare be the benefit that patients experience: are they happier and better able to pursue their goals in life? Are they better off in the long term? On the other hand, if healthcare goals are simply to avoid the appearance of certain numbers on lab tests (and on bottom lines) altogether, then perhaps we should call it "medical care" instead and admit that the main beneficiaries are medical centers. Are the boundaries of normal ranges as precisely and accurately measured as the measurements to which they are applied?

Is it right for many patients to endure hypothyroidism simply to keep more than a very few from showing numbers that suggest hyperthyroidism, however temporarily? Is patient autonomy such a dangerous thing? Is not the United States meant to be a free society, where the role of the government should be the education of its citizens and their means of protection from the unscrupulous and incompetent?  To alleviate physicians' concerns about patient autonomy, perhaps there should be a process to certify certain patients as being competent to evaluate their own clinical signs and symptoms via administered tests or other measures and to understand the major issues of their disease, but also to have that certification carry with it greater responsibility on the part of that patient.

Our healthcare system has a history of suspicion of remedies that were popular for making patients feel good in the short term, but which were life-shortening and disabling. We all know about the pitfalls of the old patent medicines and why their reliance on alcohol and opium endangered patients' health. Unfortunately, fear of patients' demands to feel "too" good, and economic pressures to rely on easily interpreted objective criteria to perform medical diagnoses have caused the medical establishment to swing to the opposite extreme, claiming increasingly that patients cannot be trusted at all to know whether they are healthy, and often insisting that misery-inducing side effects of treatment are not only tolerable but inevitable.

Why do we send physicians to medical school and then on to training as interns, residents and (sub-)specialists?  That is because medicine is in large part an art, with knowledge gained through direct experience, with the application of talent and sensitivity to human nature and its variations in health and disease. Physicians are trained, above all, to recognize individual differences and to use this knowledge to give each patient appropriate treatment.  If after all these years of training (and weeding out) a physician cannot recognize the signs of and evaluate properly the reported symptoms of common diseases, then there is something seriously wrong. 

Reforms in healthcare are increasingly dependent on "heroes" such as David Marine. Such a "hero" not only needs a vision of needed improvements, but needs to be well-credentialed and in a position of power and influence because of position, reputation and skill.  Will one come along to complete the work on "subclinical" hypothyroidism, or can our system change to accommodate a disease that so far challenges some of its most fundamental premises?


Copyright © 2013-2019 by Dorothy E. Pugh.  All rights reserved. 


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