|Coronary plaque: Is your thyroid to blame?|
The thyroid gland provides a crucial modulating role in the human body, fine-tuning function of virtually every tissue, from lowly cells at the base of the fingers making fingernails, to the neurons in your brain guiding memory and thought, to the cells lining your arteries.
Hypothyroidism, a deficiency of active thyroid hormone, can wreak devastating undesirable effects on health. When severe, signs are obvious and extravagant degrees of atherosclerosis can develop. However, mild degrees of hypothyroidism, while less dramatic, can also contribute to heart disease. Mild hypothyroidism is also proving to be far more common than previously suspected. But because it is less dramatic, it can go undetected longer, doing damage slowly over many years. It can also be more difficult to diagnose. Add to this the great debate among the medical community over the boundary between “normal” and abnormally “low” thyroid function.
The newest data have prompted a serious reexamination of what constitutes “normal” and what is “underactive.” Many people who harbor “under the radar” levels of low thyroid activity may, in fact, have low thyroid activity as an important contributor to lipid/lipoprotein abnormalities and heart disease.
It is Track Your Plaque’s mission to help identify every possible advantage for stopping or reversing plaque growth. To that end, not just clinically proper, but personally proper thyroid function may be key.
Thyroid disease: Emerging from the dark ages
For many years, the condition of hypothyroidism (hypo-, underactive) proved a mystery, doctors standing by helplessly while the patient became bloated and swollen, lost hair, became progressively weaker, often with a fatal end. While the grotesque degenerative changes that struck sufferers fascinated physicians through the ages, little insight into its causes was obtained until the late 19th century.
An elaborate description of a circa 1870’s woman in life, followed by the autopsy descriptions after her death, paint a picture of the profound nature of the disease:
“. . . there was a marked slowness of perception, and a marked slowness of response of muscles to voluntary or reflex nerve-impulse. She stated that she could not act or think quickly, that her thoughts would only come slowly; there where any operation, such as dressing, took her half an hour formerly, it now took her two hours . . . She felt always tired, so that her life was utterly wretched.”
After her death, the woman’s autopsy showed that:
“the arteries were everywhere thickened, the larger ones atheromatous . . .Overgrowths appear to have led to the obliteration of arteries, for there are many round area which look like arterial structures without a central cavity . . .”
The woman was only 54 years old.
The author, Dr. William Ord, was so struck with the edema that was evident in every organ, as well as to the naked eye, that he dubbed the condition “myxedema.” Despite the enormously detailed observations of the woman in both life and death, Dr. Ord ascribed her condition to
“. . . the evil result of a restricted indoor life, [without] the benefits of out-door exercise, of bracing air, of the exposure in journeyings by sea.”
In other words, he believed the woman didn’t get outside enough.
Yet another misguided 19th century theory was that of Nobel Prize winner Dr. Emil Theodore Kocher, the “father of thyroid surgery,” who, in 1883, noted that myxedema developed followed the surgical removal of the thyroid, but erroneously attributed the symptoms to injuries to the trachea suffered during surgery resulting in chronic asphyxia (oxygen deprivation).
Subsequent research in the later 19th and early 20th centuries pinpointed the cause of the mysterious myxedema as deficient thyroid function. Physiologist Moritz Schiff later demonstrated that animal thyroid extract administered orally could successfully correct myxedema.
While we might chuckle today at the misguided notions of the 19th century, controversy over diagnosis and management of thyroid disorders persists even today. The unfortunate woman in Dr. Ord’s description would be readily diagnosed today, but a hotly contested question remains in discerning the boundary between normal and low.
The debate is not just academic: New data suggest that not only are such factors as physical stamina impacted, but there are actual life and death implications, including lipids, lipoproteins, and coronary plaque.
The thyroid gland: A primer
The thyroid is a three inch-wide, butterfly-shaped gland located in the front of the neck. Though bridging across the trachea (airway) and located just beneath the surface of the skin, you should not be able to feel a normal thyroid. Enlarged thyroids can be felt, however.
The thyroid gland produces a collection of hormones that regulate body metabolism:
T4 (tetraiodothyronine or more commonly “thyroxine”): T4 accounts for roughly 80% of hormones produced by the thyroid. Technically, T4 is a “prohormone” or precursor hormone converted to the physically active hormone, T3, via the action of deiodinase enzymes that remove one iodine atom. T4, with an elimination half-life of about 7 days (i.e., 7 days to drop to half its level), acts as a “reservoir” for supplying the much shorter-lived T3 to the body.
T3 (triiodothyronine): T3 is the “real” thyroid hormone that controls metabolic rate at the cellular level by mediating the rate of oxygen consumption of virtually every tissue in the body. The thyroid produces only small amounts of T3 directly (roughly 15-20% of bodily requirements), relying mostly on conversion of T4 to T3 in various organs, mostly the liver and kidney. T3 is a particularly powerful hormone, such that the body requires only picogram (trillionths of a gram) quantities per deciliter of blood to function properly.
The conversion of T4 to T3 can go strangely awry: the deiodination process also creates what is known as reverse T3 (rT3), chemically similar to T3 except for the location at which T4 loses an iodine atom. rT3 is indistinguishable from T3 on most diagnostic tests. rT3 also binds to the same tissue receptor sites as T3 but is biologically inactive and blocks the action of T3. It is thought that the body regulates T3 and rT3 production as a means of raising and lowering metabolism in response to certain stimuli such as sickness, stress, and scarcity of food. (A controversial condition known as Wilson’s Syndrome, in which a disproportionate amount of rT3 is produced due to overproduction of cortisol by the adrenal glands during excessive stress, is currently being debated as the cause of certain forms of hypothyroidism.)
T2 (diiodothyronine): The thyroid produces only trace amounts of T2 with additional production occurring from the further activity of deiodinase enzymes on T3. Little is known about the effects or purpose of T2. Recent research suggests T2 may be necessary for conditions in which rapid energy utilization is required, such as cold exposure or overfeeding and may also be involved in reducing weight via regulating effects on fat storage.
T1 (monoiodothyronine): Like T2, the thyroid produces only trace amounts of T1 with additional production occurring through further deiodinase activity. T1 has no known action or effect.
The production of thyroid hormones is controlled by a series of interactions between the hypothalamus, pituitary, and thyroid gland (known as the HPT-axis):
1. The hypothalamus senses blood levels of thyroid hormones and produces increasing larger amounts of thyrotropin-releasing hormone (TRH) as thyroid hormone levels decrease.
2. TRH from the hypothalamus signals the pituitary to produce thyroid-stimulating hormone (TSH). The more TRH released, the more TSH is produced.
3. TSH signals the thyroid to produce its collection of thyroid hormones until blood levels return to normal. The HPT-axis is extremely sensitive to thyroid hormone levels, such that even small changes in circulating thyroid hormones will drive large swings in TSH levels. TSH level is therefore the primary clinical blood test measure used to diagnose hypothyroidism.
Another twist on the thyroid story: After release into the blood, T3 and T4 are transported through the body by attaching to the blood protein, thyroxine-binding globulin (TBG). T3 and T4 are only active when disassociated from TBG and in their “free” form. Reflecting their impressive potency, less than 1% of all T3 and T4 are present in their free state.
Think of the HPT-axis in terms of your home heating system. The hypothalamus and pituitary are similar to the heat sensor in your thermostat. The thyroid can be thought of as your furnace, the device that actually produces the heat. Under normal operating conditions the system functions in unison to maintain the proper temperature (quite literally in the case of the thyroid and body temperature).
The system can fail at many points. However, failure of the thyroid gland itself (so-called primary hypothyroidism) is by far the most common condition; we will focus on this question. (Failure of the pituitary or hypothalamus, so-called secondary and tertiary hypothyroidism, are rare and not discussed here.)
Thyroid disease basics
Disorders of the thyroid come in a variety of shapes and sizes, but can be broken down into two general categories: hypothyroidism (underactive thyroid) and hyperthyroidism (overactive thyroid). By a wide margin, hypothyroidism is the more insidious that often evades diagnosis, unrecognized for years while contributing to growth of coronary plaque. Hyperthyroidism, while important, carries less implication for our plaque-control efforts and will therefore not be the focus of our discussion.
Hypothyroidism is a condition in which the thyroid produces inadequate amounts of thyroid hormones, primarily T4 and T3. It is typically categorized as either overt or subclinical hypothyroidism based on standard blood testing and severity of symptoms.
Overt hypothyroidism nowadays tends to be recognized before it reaches the extreme stage of Dr. Ord’s day, manifesting itself by high TSH levels (>10mIU/L) and usually accompanied by one or more pronounced symptoms including:
* Substantial drop in energy; fatigue, trouble awakening in the morning, need for more sleep, and tendency to fall asleep during the day
* Feeling cold when other people feel warm; less sweating
* Drier, itchier skin
* Yellow or orange skin, caused by a build-up of the pigment carotene from fruits and vegetables
* Dry, coarse, brittle hair; hair loss or thinning
* Loss of appetite but with paradoxical weight gain (5-20 pounds) and difficulty losing weight
* Short-term memory impairment, slower thinking
* New snoring
* More frequent and severe muscle cramps and joint aches
* Feelings of pins and needles in the hands and feet (paresthesia)
* New constipation
* New puffiness around the face (especially the eyes), hands, ankles, and feet due to fluid build-up
* Carpal tunnel syndrome
* Heavier and/or more frequent menstrual periods, worse cramps, worse premenstrual symptoms
* New depression, sadness or not caring about anything
* New hoarse voice
* New hearing loss
* Goiter (swelling in the front of the neck, caused by enlargement of the thyroid)
* Shrinking thyroid (most likely in atrophic thyroiditis)
* Abnormally slow heart rate
* Slightly higher diastolic (“bottom number”) blood pressure
* Iron deficiency anemia, low ferritin (an iron storage protein)
* Kidney dysfunction
Diagnosing hypothyroidism is often difficult if based purely on symptoms, as there is no single symptom specific to hypothyroidism. Symptoms are also often vague. Levels of thyroid hormones, free T3 and T4, along with TSH, therefore are used to confirm the diagnosis.
Diagnosis can be especially troublesome in lesser degrees of underactive thyroid function, or subclinical hypothyroidism. Subclinical hypothyroidism is so named because patients may present with “normal” blood test results yet often exhibit some of the above symptoms, though perhaps less severe. The frequency of hypothyroidism increases with age and, though estimates vary due to differing cut-points for TSH, most estimates cite a range of 2-4% early in life to as high as 15-20% later in life, with greater prevalence in females (Andersen S et al 2002).
While no test for thyroid activity by itself is perfect, the most sensitive blood test is the TSH blood level. Despite its shortcomings, TSH remains the primary method of confirming that symptoms may be attributable to hypothyroidism. Unfortunately, there is fundamental disagreement about what constitutes a “normal” TSH level.
The standard (though disputed) TSH ranges (in mIU/L) from the American Thyroid Association are listed below.
0.0 – 0.4 Hyperthyroidism
0.4 – 2.5 Normal Range
2.5 – 4.0 At Risk: (repeat TSH test at least once a year)
4.0 – 10.0 Sub-clinical (mild) hypothyroidism
Above 10.0 Hypothyroidism
Other commonly used laboratory tests to gauge thyroid function include:
Free T4 (fT4) and free T3 (fT3): These are the preferred tests that measure T4 and T3 not bound to a protein and are therefore active, excluding the 99.9% of hormone bound to proteins. If total T4 or T3 levels (see below) are normal yet free T4 or T3 levels are low it may indicate an overproduction or excessive affinity of binding proteins, thereby reducing bioavailability of free T4 or T3. Reference ranges for free T4 and T3 should be supplied by the test lab along with the result. As with TSH, what is “normal” for the standard population may not be normal for each individual and there can be considerable differences in the T4 or T3 levels ideal for each person. Some have argued that T3 and T4 levels should be in the upper third of the reference range to be ideal, or to tailor levels to symptom relief.
Total T4, total T3: As its name implies, these tests measure total T4 or T3, bound and unbound, in a blood sample. However, this test can be misleading, since most T4 and T3 (99.9%) is bound to proteins, which render it unusable by the body’s tissues. However, total T4 and T3 may be useful as a measure of total thyroid output.
T4 uptake and T3 uptake: Before the advent of modern radioimmunoassay (RIA) techniques, this test was used in conjunction with total T4 and T3 to indirectly calculate free T4 and T3. These tests have been replaced by direct measurement of free T4 and free T3 using RIA and should therefore not be used.
High TSH tests and/or low total and low free T4/free T3 tests will likely trigger the need for additional tests to determine if the source of deficient thyroid function is the thyroid itself. The most frequently used tests are:
Thyroid Peroxidase Antibody (TPO Ab) Test: Thyroid peroxidase (TPO) is a thyroid enzyme responsible for making iodine available as part of the process for manufacturing thyroid hormones. A common autoimmune condition results in the body attacking the TPO enzyme. Approximately 90% of sufferers of the inflammatory thyroid disorder, Hashimoto’s thyroiditis, will test positive for elevated TPO antibodies (Carlé A et al 2006).
Thyroglobulin Antibody (TG Ab) Test: Another common autoimmune condition results in the body attacking thyroglobulin. Approximately 60% of Hashimoto’s thyroiditis sufferers will test positive for elevated thyroglobulin antibodies. Testing positive for both TPO and TG antibodies increases the likelihood of Hashimoto’s thyroiditis to 95% (Carlé A et al 2006).
Basal Body Temperature (BBT) Test: This procedure involves recording the body temperature; low temperatures can indicate hypothyroidism. If a thermometer is placed under the armpit for 10 minutes immediately after waking and repeated daily for 3-5 days, temperatures below 97.6F can indicate hypothyroidism. However, this test should never be used by itself to diagnose an underactive thyroid, but should be viewed in the context of other laboratory information and symptoms.
The Role of Hypothyroidism in Coronary Plaque and Heart Disease
Hypothyroidism, including subclinical hypothyroidism, has been linked to both coronary heart disease and distortions in lipid and lipoprotein patterns.
It is well-established association, hypothyroidism raises LDL cholesterol. The higher the TSH (less active thyroid hormone), the higher LDL cholesterol (and apoprotein B and LDL particle number) tend to be.
Although the blunted metabolic state of an underactive thyroid reduces LDL cholesterol production, cellular uptake of LDL is reduced to a greater degree, resulting in net accumulation of LDL. The Basel Thyroid Study was the first double-blind, placebo-controlled study of its kind that suggested that “L-thyroxine replacement in patients with subclinical hypothyroidism has a beneficial effect on low density lipoprotein cholesterol levels and clinical symptoms of hypothyroidism. An important risk reduction of cardiovascular mortality of 9–31% can be estimated from the observed improvement in low density lipoprotein cholesterol” (Meier C et al 2001). This relationship has been confirmed across a number of studies in thousands of subjects (Iqbal A 2006; Canaris GJ 2000). For most people, correction of thyroid hormone deficiency leads to reduction in LDL and Apo B, with a larger effect in those with the highest TSH levels (more severe hypothyroidism). In persons with subclinical hypothyroidism, LDL and Apo B reductions of 20 mg/dl are typical (Monzani et al 2004).
The HUNT Study likely closes the door for good on this argument. This large Norwegian study examined the thyroid hormone levels of an initial 35,000 people. Thyroid hormone levels were then correlated with various parameters. As in previous studies, a clear relationship between higher TSH levels and higher LDL levels was observed. However, the HUNT Study was unique not only for the extraordinary size of the group studied, but because the investigators extended the analysis to TSH levels ordinarily considered within the normal range. In this analysis, a TSH level 1.0 mIU marked the start of a gradual increase in LDL. In other words, it wasn’t until TSH levels were 1.0 or less that it ceased to be associated with higher levels of LDL cholesterol (Asvold B 2007).
What about small vs. large LDL? Here the data are not so clear, with conflicting observations. However, the best information emerges from the one study that used NMR lipoprotein analysis, which suggested that the larger, less atherogenic (plaque-causing) fraction increased (actually doubled) preferentially with lower thyroid function (higher TSH). This suggests that, while LDL cholesterol increases with diminishing thyroid and rising TSH, it is the less harmful large fraction (Pearce E 2008).
Oxidized LDL may be more likely to contribute to coronary plaque by triggering ingestion by macrophage inflammatory cells. Higher TSH levels in both overt and subclinical hypothyroidism are associated with greater levels of oxidized LDL; correction of hypothyroidism reversed the oxidized state (Duntas LH et al 2002).
In the HUNT Study, as TSH increased above 1.0 mIU, LDL increased, but HDL decreased. However, the effect is quite small, amounting to a difference of no more than 2 mg/dl. This is similar to the finders of other studies.
As you might expect, along with increases in LDL, hypothyroidism is accompanied by increased triglycerides; the higher the TSH, the higher the triglycerides. The degree of increase roughly parallels the change in LDL, though is slightly less (usually 10-20 mg/dl in subclinical hypothryoidism; Asvold BO et al 2007). Correction of hypothyroidism also reduces triglycerides.
While increasing levels of homocysteine are associated with increasing levels of cardiovascular risk, several randomized clinical trials have failed to show substantial reduction of risk with correction of homocysteine using a combination of B vitamins (folic acid, B6, B12). Nonetheless, the observation that hypothyroidism is associated with higher homocysteine and correction of hypothyroidism leads to reduction of homocysteine (-44%) raises some interesting questions about the thyroid’s role behind homocysteine as a predictor of cardiovascular events (Hussein W et al 1999).
Could homocysteine serve, at least to a degree, as a surrogate for low thyroid function? While some authorities are ready to dismiss homocysteine as a dead end, significant questions remain that may, in time, yield important insights into just what role homocysteine should play in our coronary plaque control efforts.
Until then, a high homocysteine (>10 µmol/L) should at least cause us to consider an underactive thyroid gland as a contributor.
As with all other things lipoprotein(a), thyroid issues provide a frustratingly variable collection of observations: the higher the TSH (low thyroid), the higher the Lp(a)?usually . . . but not always.
While a number of studies have shown that higher TSH levels are clearly associated with higher Lp(a), other studies have shown no relationship. In some studies, there are even subjects who show a modest increase in Lp(a) when a low thyroid state is corrected (Kung AWC et al 1995). There are nonetheless an important subset of people who do show substantial reductions in Lp(a) of 30-60 mg/dl with thyroid correction.
As with most other experiences with Lp(a), the data suffer from variation in the method of Lp(a) measurement and the tremendous genetic variation in Lp(a) types (Kung AWC et al 1995; Becerra A et al 1999; Tzotzas T et al 2000; Yildirimkaya M et al 1996) . In Lp(a), “what works for Peter may not work for Paul.” Another factor is time: Lp(a), for unclear reasons, requires at least 3-4 months to respond to any intervention; reassessment before this time period yields misleading results (Kung AWC et al 1995).
What about the relative effects of T3 vs. T4 replacement? There are not a lot of data, but limited experiences do suggest that T3 may contribute to Lp(a) reduction, such as a small Dutch study in patients after thyroid removal, in which T3 only supplementation reduced Lp(a) up to 50 mg/dl (Dullart RP et al 1995). Whether adding T3 to T4 treatment adds to Lp(a)-reducing effect has not been systematically examined, but anecdotally seems to add a small advantage.
Thyroid hormones, especially T3, enhance the action of nitric oxide in the arterial wall, which causes a modest reduction in arterial tone and blood pressure. This effect is similar to that of l-arginine. People with subclinical hypothyroidism have been observed to have impaired artery dilating responses, corresponding to a rise in diastolic blood pressure, an effect which reverses when hypothyroidism is treated (Taddei S et al 2003).
Heart rate and parasympathetic tone
Curiously, despite the slowed metabolic rate of hypothyroidism, heart rate is usually not slowed and is indistinguishable from people with normal thyroid function.
However, beat-to-beat variation in the interval from one heart beat to the next is a desirable feature, a condition of heightened parasympathetic (opposite of sympathetic “fight-or-flight”) tone; increased variability is seen in healthy people, high levels of fitness, people who meditate. People with hypothyroidism display diminished beat-to-beat variability, reflecting impaired parasympathetic tone, a potential marker for poor health and adverse outcomes (Kahaly GJ 2000).
C-reactive protein (CRP) is widely viewed as a marker for various inflammatory processes that accelerate heart disease. Hypothyroidism and subclinical hypothyroidism increases CRP modestly. However, it is not clear whether correction of hypothyroidism leads to reduction of CRP (Mirjam CG et al 2003; Nagasakia T et al 2007).
Hypothyroidism and coronary plaque
Not only has both overt and subclinical hypothyroidism been associated with worsening factors in the coronary risk profile (above), but it has also been associated with increased risk of heart attack.
Among the several analyses emerging from the Rotterdam Study, a study of 1149 women showed that participants with TSH >4.0 mU/L showed a 70% greater likelihood of aortic atherosclerosis (judged by simple x-ray of the aorta) and more than double the likelihood of heart attack (Hak AE et al 2000).
Though individual studies vary widely in the magnitude of increased risk with subclinical hypothyroidism (as high as 80% in a 2005 study; Walsh JP et al 2005), in an analysis of 10 combined studies (a “meta-analysis”) examining a total of 14,500 participants, subclinical hypothyroidism was associated with a 20% increase in risk for heart attack (Ochs N et al 2008). A small study using coronary angiography showed that 5 of 7 people with “adequate” thyroid replacement (150 mcg levothyroxine) showed no progression of coronary disease, compared to a group “inadequately” treated (<100 mcg levothyroxine) all of whom showed progression (Perk M, O’Neill BJ 1997).
The HUNT Study extended these observations by analyzing risk of fatal cardiovascular events over eight years along the entire spectrum of TSH levels, even into the “normal” reference range <3.5 mU/L. By breaking their groups down by TSH levels, the group with TSH 1.5-2.4 mU/L showed a 41% increase in events; the group with TSH 2.5-3.5 mU/L showed a 69% increase in events, when both groups were compared to the group with TSH 0.50-1.4 mU/L. However, the relationship was stronger in women than in men (Asvold BO et al 2008).
Is the discussion so far just academic if you have coronary plaque? In other words, does reduction of TSH and correction of low thyroid pose any advantage in reducing risk of heart attack or reduce coronary atherosclerotic plaque?
That question has not yet been fully explored. However, an Italian study of 45 people with subclinical hypothyroidism (median TSH 6.31 mU/L) compared to 32 controls (median TSH 1.19 mU/L) demonstrated that those with hypothyroidism began with higher LDL cholesterol levels (+25 mg/dl), equivalent HDL levels, higher triglycerides (+14 mg/dl), higher Lp(a) (3 mg/dl); greater carotid intimal-medial thickness (CIMT; +19%), a measure of atherosclerosis in the carotid artery. After 6 months of treatment with T4 to achieve TSH of 1.32 mU/L, the participants with starting hypothyroidism showed an 11% regression of CIMT. In addition, LDL was reduced by 20 mg/dl; Apo B by 9 mg/dl; triglycerides by 6 mg/dl; Lp(a) by 2.3 mg/dl (Monzani F et al 2004).
Treatment options for hypothyroidism
A battle is raging between two opposing camps.
One side consists of traditional practitioners, including most endocrinologists, primary care physicians, and their professional organizations, that advocate treatment using only synthetic T4 compounds with diagnosis and dosing based on TSH levels. The other side portrays itself as self-styled, cutting-edge physicians and patient advocates who recommend relying primarily on symptoms, an extended set of tests, and the use of natural hormone products to treat thyroid deficiencies in certain cases.
Traditional Medical Treatment of Hypothyroidism
Since the discovery of synthetic T4 (levothyroxine) in the late 1950’s and the development of sensitive, low-cost tests for TSH, the traditional medical community has come to rely almost exclusively on this simple and successful combination of diagnosing and treating hypothyroidism. It allows primary care physicians to identify patients suffering from clinical hypothyroidism and effectively treat them without the time and cost of referring patients to specialists. The argument for this protocol is based on the observations that:
* Elevated TSH is a consistent and sensitive method for detecting an under-active thyroid for a large portion of the population.
* If necessary, TSH tests can be complimented with other tests to confirm a diagnosis of hypothyroidism.
* Current TSH reference ranges identify the overwhelming majority of cases of hypothyroidism.
* Synthetic T4 has a consistent track record of effectiveness and tolerability. Synthetic T4 is identical to human T4. Natural products, in contrast, are derived from animal thyroids and therefore contain proteins not normally found in the human body.
* Although synthetic T4 monotherapy does not replace T3 or other trace hormones produced naturally by the thyroid, most T3 in the body is derived from T4 (as are T2 and T1 via deiodination) and there is conflicting evidence that direct replacement of T3 or other thyroid components adds benefit.
It is also commonly argued that synthetic T4 is manufactured under exacting pharmaceutical standards and is a more stable and consistent product than replacement thyroid preparations compounded from animal sources.
The “other side”
Practitioners and patient advocates who disagree with conventional wisdom argue that:
* TSH and other thyroid blood tests are not sensitive enough to detect all persons with hypothyroidism. Many will show “normal” values, particularly those with mild or subclinical hypothyroidism. Levels considered normal for an average population may be too wide due to person-to-person variability of TSH, T4, and T3 levels, yielding an unacceptable number of false negatives. They also argue that TSH serves as an unreliable index of pituitary function in many people and can be falsely low even when hypothyroidism is truly present. Recent data appear to support this argument, with one recent study showing that, as we age, the increase in TSH with low thyroid function is 75% less compared to younger people (Carlé A et al 2007) They propose that attention to symptoms is essential for detecting persons suffering from hypothyroidism missed by standard laboratory testing.
* Synthetic T4 is not sufficient to resolve the symptoms of a large number of persons with hypothyroidism. T4 is depicted as an “unnatural” way to supplement lost thyroid function, since not everyone converts T4 to active T3 with equal efficiency. Indeed, low-T3 has been documented to be a predictor of death in patients with congestive heart failure (Iervasi G et al 2003). T3 supplementation appears to have positive effects on psychological symptoms of hypothyroidism with several studies showing that well-being, mood, and other neurocognitive functions are improved; weight loss may also be greater with added T3 (Saravanan P et al 2002; Bunevicius R et al 1999; Appelhof BC et al 2005). T3 supplementation tailored to symptom relief may also address the issue of reverse T3 by providing an external source of effective T3 (Gaby A 2004).
* Claims that synthetic T4 drugs are superior to natural thyroid drugs in consistency, potency, and stability are false. The hormones found in porcine (pig) thyroid are chemically identical to that found in humans. It also seems dubious to obsess over animal proteins, as they are regularly consumed whenever eating ham, pork chops, or bacon. While this may pose a problem on certain religious grounds, it should offer no impediments on medical grounds. Claims of impurity also appear to be a misrepresentation propagated by pharmaceutical marketing. In fact, both Synthroid® (synthetic T4) and Armour Thyroid (porcine thyroid) have both had similar struggles with potency and stability in past. Unfortunately, many doctors and patients have only heard about problems with Armour Thyroid. The Department of Health and Human Services has twice issued cease and desist orders to the manufacturer of Synthroid® for misleading advertising. Prior to the development of synthetic T4 in the 1950’s, natural thyroid hormone products were the only treatment for hypothyroidism since their introduction in the late 1800’s. In that time, they developed an extensive track record for safety and efficacy, and products such as Armour Thyroid are now produced under the same USP standards as synthetic T4.
In the Track Your Plaque experience, we’ve sided with the second group that favors more symptom management over TSH, assessment of T3 as well as T4, and the use of natural thyroid preparations like Armour Thyroid over levothyroxine or Synthroid®. For anyone who wishes to add T3 but wants to avoid the animal-sourced product, a synthetic T3 is also available (by prescription).
In addition to this ongoing debate, there are several other issues not addressed here but will be addressed in the Track Your Plaque Compete Handbook of Hypothyroidism and the Heart, such as the role of adrenal insufficiency and iodine deficiency.
Subclinical hypothyroidism & the Track Your Plaque program: practical tips
The data, studies, references, inferences, and opinions offered in this Report can be condensed into a few yet powerful guidelines for heart disease sufferers:
* All levels of hypothyroidism, regardless of how mild, appear to increase heart disease risk. Risk for cardiovascular events may extend to TSH levels as low as 1.4 mU/L.
* Traditional clinical methods of diagnosing hypothyroidism, especially subclinical hypothyroidism, can be deficient in some people. Strong arguments can be made for further testing and attention should be paid to symptoms in arriving at a diagnosis.
* Strict adherence to synthetic T4 (i.e., levothyroxine, Synthroid®) to treat hypothyroidism may not represent optimal treatment in everyone. Natural hormone therapy (e.g., Armour Thyroid) that provides T3 replacement may be more efficacious for some people with hypothyroidism. Lower levels of T3 and/or less than optimal symptoms relief on T4 alone may suggest potential for benefit by adding T3 or converting to a preparation like Armour Thyroid.
* Correction of hypothyroidism and subclinical hypothyroidism can reduce LDL, triglycerides, Lp(a), possibly homocysteine and C-reactive protein, and may help normalize endothelial function. Preliminary experiences suggest that it may also facilitate atherosclerotic plaque regression.
TAndersen S, Pedersen K, Bruun NH et al. Narrow individual variation in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease J Clin Endocrinol Metab 2002; 87:1068-72.
Appelhof BC, Fliers E, Wekking EM et al. Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab 2005;90(5):2666-74.
Åsvold BO, Bjøro T, Nilsen TI et al. Thyrotropin levels and risk of fatal coronary heart disease (The HUNT Study) Arch Intern Med 2008;168(8):855-860
Becerra A, Bellido D, Luengo A, Piédrola G, De Luis DA. Lipoprotein(a) and other lipoproteins in hypothyroid patients before and after thyroid replacement therapy, Clin Nutr. 1999 Oct;18(5):319-22.
Bunevicius R, Kazanavicius G, Zalinkevicius R et al. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism, N Engl J Med. 1999 Feb 11; 340(6):424-9.
Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado Thyroid Disease Prevalence Study. Arch Int Med 2000;160:526-34.
Carlé A, Laurberg P, Knudsen N et al. Thyroid peroxidase and thyroglobulin auto-antibodies in patients with newly diagnosed overt hypothyroidism. Autoimmunity 2006 Sep;39(6):497-503.
Carlé A, Laurberg P, Pedersen IB et al. Age Modifies the Pituitary TSH Response to Thyroid Failure. Thyroid 2007 Feb;17(2):139-44.
Dullart RP, van Doormaal JJ, Hoogenberg K, Sluiter WJ. Triiodothyronine rapidly lowers plasma lipoprotein (a) in hypothyroid subjects. Neth J Med 1995 Apr;46(4):179-84.
Duntas LH, Mantzou E, Koutras DA. Circulating levels of oxidized low-density lipoprotein in overt and mild hypothyroidism. Thyroid 2002;12:1003-7.
Gaby A. "Sub-laboratory" hypothyroidism and the empirical use of Armour® Thyroid. Altern Med Rev; 2004 June.
Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 2000;132:270–278
Hussein WI, Green R, Jacobsen DW, Faiman C. Normalization of hyperhomocysteinemia with l-thyroxine in hypothyroidism. Ann Intern Med 1999; 131:348-51.
Iervasi G, Pingitore A, Landi P, et al. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 2003 Feb 11;107(5):708-13.
Iqbal A, Jorde R, Figenschau Y. Serum lipid levels in relation to serum thyroid-stimulating hormone and the effect of thyroxine treatment on serum lipid levels in subjects with subclinical hypothyroidism: The Tromsø Study. J Intern Med 2006 Jul;260(1):53-61.
Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical hypothyhroidism. Thyroid 2000;10:665-79.
Kung AWC, Pang RWC, Janus ED. Elevated serum lipoprotein(a) in subclinical hypothyroidism Clinical Endocrinology 1995;43(4): 445–49
Meier C, Staub JJ, Roth CB et al. TSH-controlled l-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: A double blind, placebo-controlled trial (Basel Thyroid Study). J Clin Endocrinol Metab 2001;86(10)4860-66.
Mirjam CG, Christian M, Merih G et al. Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and double-blind placebo-controlled trial. Atherosclerosis 2003;166(2):379-86
Monzani F, Caraccio N, Kozàkowà M et al. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: A double-blind, placebo-controlled study. J Clin Endocrinol Metab 2004;89(5):2099-106.
Nagasakia T, Inabaa M, Shirakawaa M. Increased levels of C-reactive protein in hypothyroid patients and its correlation with arterial stiffness in the common carotid artery. Biomed Pharmacother 2007; 61:167-72.
Olivieri O, Girelli D, Stanzial AM et al. Selenium, zinc, and thyroid hormones in healthy subjects: low T3/T4 ratio in the elderly is related to impaired selenium status, Biol Trace Elem Res. 1996 Jan;51(1):31-41.
Saravanan P, Chau WF, Roberts N et al. Psychological well-being in patients on ‘adequate' doses of l-thyroxine: Results of a large, controlled community-based questionnaire study. Clin Endocrinol 2002;57(5):577–585.
Taddei S, Caraccio N, Virdis A et al. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab 2003;88:373137.
Tzotzas T, Krassas GE, Konstantinidis T, Bougoulia M., Changes in lipoprotein(a) levels in overt and subclinical hypothyroidism before and during treatment. Thyroid. 2000 Sep;10(9):803-8. ncbi.nlm.nih.gov
Walsh JP, Bremner AP, Bulsara MK et al. Subclinical Thyroid Dysfunction as a Risk Factor for Cardiovascular Disease Arch Intern Med. 2005;165:2467-2472.
Yildirimkaya M, Ozata M, Yilmaz K et al. Lipoprotein(a) concentration in subclinical hypothyroidism before and after levo-thyroxine therapy, Endocr J. 1996 Dec;43(6):731-6.
Copyright 2008, Track Your Plaque.