High Cholesterol? CVD Risk? It Might Be Your Thyroid

I’ve written enough articles on thyroid disorders to fill an entire eBook: all about low T3 syndrome, five thyroid patterns that won’t show up on standard lab tests, the little-known cause of hypothyroidism, and the gut–thyroid connection.

Thyroid hormone regulates a great deal of metabolism, and virtually every cell in the body has a receptor for thyroid hormone. In a recent podcast, I mentioned poor thyroid function as one of the six underlying causes of high cholesterol. In this article, I’ll discuss exactly how your thyroid impacts lipid metabolism, cholesterol levels, and other risk factors for cardiovascular disease. First, though, a quick review of the major hormones involved.

A Quick Review of Thyroid Physiology and Lab Panels

The thyroid is a small butterfly-shaped gland that sits at the front of the neck. It receives a hormone signal from the pituitary and secretes other hormones into the bloodstream. You might be familiar with these hormones, which are included in a full thyroid panel:

Thyroid-stimulating hormone (TSH): This hormone is released by the pituitary gland and reflects the body’s need for thyroid hormone. This means that when TSH is high, not enough thyroid hormone is being produced (hypothyroidism). When TSH is low, there is more than enough thyroid hormone in the body (hyperthyroidism).

Do you have heart disease or high cholesterol? You might want to get your thyroid checked

Thyroxine (T4): The thyroid gland releases large amounts of this largely inactive form of thyroid hormone, which must be converted into the more active T3 by deiodinase enzymes. Low amounts of T4 may indicate hypothyroidism; high amounts may indicate hyperthyroidism.

Triiodothyronine (T3): This is the active form of thyroid hormone, secreted in small amounts by the thyroid gland and formed from the conversion of T4 to T3. T3 is the primary thyroid hormone that will act on cells all over the body to regulate metabolism. Low amounts of T3 may indicate hypothyroidism or low T3 syndrome; high amounts indicate hyperthyroidism.

If thyroid medication is given for hypothyroidism, it is usually in the form of T4, T3, or a combination of the two.

The Association between Thyroid Hormone Levels and Cholesterol

Today, a PubMed search for thyroid and cholesterol yields more than 3,000 articles—yet few people, and even few doctors, are aware of how various thyroid conditions can impact cholesterol levels.

Let’s review the four major types and how they impact basic cholesterol measurements:

Hypothyroidism: People with an underactive thyroid, or hypothyroidism, often have increased levels of total cholesterol and LDL cholesterol (2) and may have elevated triglyceride levels as well (3). Thyroid medication can significantly improve lipid profiles. A study in newly diagnosed hypothyroid patients found that total cholesterol and LDL cholesterol levels decreased after T4 treatment. Those with higher TSH levels (indicating a greater need for thyroid hormone and a greater degree of hypothyroidism) at baseline saw a more dramatic reduction in cholesterol levels with T4 therapy (4).

Subclinical hypothyroidism: Subclinical hypothyroidism (SH) is characterized by elevated serum TSH with normal levels of free T4 and free T3. Subclinical hypothyroidism is far more common than overt hypothyroidism and may affect up to 9 percent of the population (5). Studies are mixed on the effect of subclinical hypothyroidism on lipid profiles, but even within the normal range of values, increasing TSH is associated with an increase in total cholesterol and LDL cholesterol (6, 7). One systematic review found that T4 substitution therapy on average resulted in an eight mg/dL decrease in total cholesterol and a 10 mg/dL decrease in LDL cholesterol in people with subclinical hypothyroidism (8).

Thyroid autoimmunity: Autoimmunity is a major cause of hypothyroidism. An estimated 90 percent of people with underactive thyroid have autoimmune thyroiditis, also known as Hashimoto’s disease. People with high-normal TSH levels that have positive anti-thyroid antibodies are even more likely to have abnormal cholesterol levels. On the bright side, their cholesterol levels are more likely to respond to thyroid medication (9).

Hyperthyroidism: While not as common, hyperthyroidism is associated with low levels of total cholesterol, HDL cholesterol, and LDL cholesterol (10, 11). While this may seem like a good thing, low blood cholesterol has been associated with altered cell membrane function, depression, anxiety, memory loss, and increased mortality (12, 13, 14).

How the Thyroid Regulates Lipid Metabolism

Fair warning, this section contains the nitty gritty details of lipid metabolism. If you’re not in the mood for a physiology lesson, you can skip on to the next section!

Thyroid hormones regulate cholesterol synthesis

You may have heard that dietary cholesterol doesn’t have much impact on blood levels of cholesterol. This is because cholesterol is also synthesized by the liver. This process is tightly regulated by several hormones, including thyroid hormones. TSH increases the expression and activity of an enzyme called HMG CoA reductase, which controls the rate of cholesterol synthesis (15). This means that hypothyroidism increases the amount of cholesterol produced in the liver. This cholesterol is then packaged with triglycerides into VLDL particles, which are shipped out to the bloodstream.

Thyroid hormones affect lipoprotein lipase (LPL)

VLDL particles travel through the bloodstream until they reach the small blood vessel beds, where they encounter an enzyme called lipoprotein lipase (LPL). This enzyme breaks down the triglycerides in the VLDL particle into fatty acids, which are taken up by adipose, heart, and muscle cells. T3 stimulates LPL to increase this breakdown of triglyceride-rich VLDL (16). Eventually, the cholesterol content of the lipoprotein becomes higher than the triglyceride content, and these particles become LDL.

Thyroid hormones increase LDL particle uptake

LDL particles circulate around in the blood until they bind to LDL receptors. This binding triggers the capturing of LDL particles into the cell. There, the LDL particles are degraded and the contents used for cell membrane structure or converted to other steroid hormones. Through several mechanisms, T3 increases the expression of LDL receptors (17, 18). This reduces the amount of time that LDL particles spend circulating in the blood and the total number of LDL particles in the blood.

Thyroid hormones affect LDL particle oxidation

Excess LDL particles in the blood can cause some particles to “crash” into the blood vessel wall and be taken into the inner lining of the blood vessel. Once there, the LDL particles can become oxidized, which triggers inflammation and is thought to be the major event initiating the formation of arterial plaque. T3 acts as a free radical scavenger and may protect LDL from oxidation (19). However, high free T4 can also enhance LDL oxidation (20). Thus, both hypo- and hyperthyroidism can lead to LDL oxidation.

The Dangers of Statins in People with Thyroid Dysfunction

If you’ve been following my work for a while, you probably know my opinion of statin drugs. Here are just a few of the articles I’ve written on statins:

• The truth about statin drugs
• What the media isn’t telling you about statin drug trials
• The diet–heart myth: statins don’t save lives in people without heart disease

But it turns out that statin use is particularly concerning when the cause of high cholesterol is poor thyroid function. This is due to the effects of statins on creatine kinase levels.

Creatine kinase (CK) is an enzyme expressed in many different tissues throughout the body, though it’s probably most well-known for its action in muscle cells. CK is responsible for adding a phosphate to creatine to form phosphocreatine, which serves as an energy reservoir and allows for the quick release of energy in times of need.

Both statins and hypothyroidism result in CK release into the blood, and the cumulative effect is severe CK elevation (21, 22). This can potentially amplify the adverse side effects of statins.

Yet, in reviewing the relevant medical records of 77 patients treated receiving statins in a hospital, a team of medical researchers discovered that only 23 percent of patients had received a thyroid panel before beginning statin treatment. Worse yet, 12 percent of patients with overt hypothyroidism received statins without receiving a thyroid panel or hypothyroid diagnosis (21).

The authors commented on their findings, emphasizing the need for routine thyroid screening in patients with lipid abnormalities:

We must not begin and continue to use these drugs without checking the possibility of hypothyroidism. (21).

Statin drug information in Japan and the UK now includes warnings that emphasize the need for careful use in patients with hypothyroidism. The same cannot be said for the United States or in other countries. Thus, it’s very important to exclude other diseases that cause high cholesterol, such as hypothyroidism, diabetes, and kidney dysfunction, before even considering taking a statin.

Better Markers of Cardiovascular Risk

Wait, but I thought cholesterol tests were out—aren’t lipoprotein particle numbers what we really care about?

Yep. I’ve discussed in several articles and on my podcast why lipoprotein particle numbers are much better predictors of cardiovascular risk than cholesterol levels. However, there are few studies that have assessed the effects of thyroid hormones on lipoprotein particle number, compared to the number of studies that have assessed standard cholesterol measurements. Still, we see similar effects:

• LDL particle number (LDL-P): Subclinical hypothyroidism has been associated with higher levels of ApoB-100, a surrogate marker for LDL particle number. T4 treatment significantly reduced ApoB-100 levels (25).
• Oxidized LDL: Decreased thyroid function increases the number of LDL particles and promotes LDL “oxidizability” (26).

Thyroid health also impacts other cardiovascular risk factors:

• Blood pressure: Underactive thyroid is strongly associated with hypertension. This is due to both sympathetic and adrenal activation (27). One study of 30 patients with both hypothyroidism and hypertension found that hypertension was reversed in 50 percent of patients after thyroid medication therapy (28).
• C-reactive protein (CRP): CRP, a marker of inflammation, has been shown to be negatively correlated with levels of free T4 (29). Patients with subclinical hypothyroidism have also been found to have increased CRP (30).
• Lipoprotein(a) (Lp(a)): Lp(a) is a measure of how many lipoprotein particles are carrying apolipoprotein A1. Apolipoprotein A1 has a high affinity for oxidized lipids and is thought to be largely based on genetics. Patients with overt hypothyroidism and subclinical hypothyroidism have increased Lp(a) (31, 32). Some studies of subclinical hypothyroidism patients suggest that thyroid medication can reduce Lp(a) (33), but others found no significant change (34).
• Phospholipase A₂ (Lp-PLA₂): This is an enzyme that travels largely with LDL particles, is highly pro-inflammatory, and is involved in the development of atherosclerosis (35). Subclinical hypothyroidism subjects have been shown to have higher Lp-PLA₂ (36).
• Homocysteine: Hypothyroidism is associated with increased plasma homocysteine levels (37)
• Insulin resistance and BMI: Insulin resistance and a high BMI are both positively correlated with low thyroid function (38, 39).

Conclusion

I hope I have convinced you that thyroid function plays a major role in lipid metabolism. I can’t tell you the number of patients I have seen in my clinic with lipid abnormalities that had undiagnosed thyroid conditions. Restoring thyroid health by correcting nutrient deficiencies, rebalancing the immune system, and making simple diet and lifestyle changes can often make a major difference in cholesterol levels and cardiovascular risk markers. In some cases, thyroid support in the form of medication may also be helpful and is much less harmful than statins.

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