Hypothyroidism and high cholesterol

Hypothyroid and Cholesterol: Too Little Thyroid Hormone, Too Much Cholesterol

With Arjola Bano, MD, DSc and Elizabeth N. Pearce, MD

Certainly, having a thyroid disorder is no picnic but understanding the ways in which your thyroid can affect how your body functions is an important first step toward feeling better. A growing body of research finds that both overt and subclinical hypothyroidism can put you at a greater risk for high blood cholesterol, a leading and controllable cause of cardiovascular disease.1

Fortunately, keeping your thyroid in balance will help keep your cholesterol in check. Even better: knowing your heart disease risk means you can be proactive with preventative measures so you’ll be helping improve your thyroid health while simultaneously staying heart-healthy.

Hypothyroidism like Hashimoto’s thyroiditis may lead to increased risk for heart disease. Both require proper management.

Hypothyroidism and High Cholesterol: A Look at the Relationship

Most of the cholesterol circulating in your blood is produced in your body, specifically the liver. The body needs cholesterol to carry out all sorts of important functions, such as: strengthen cell membranes, make hormones, fat-soluble vitamin, and bile acids that are needed to help digest fat. But like all good things, too much cholesterol can become a bad thing, even deadly. You may have heard that there are two types of cholesterol. The so-called bad cholesterol is known as low-density lipoprotein (LDL) and high-density lipoprotein, or HDL, is the kind of blood cholesterol you want more of since it is protective. Too much bad cholesterol or not enough good cholesterol typically leads to a buildup of the cholesterol plaque in the arteries, which raises your risk for heart disease and stroke.

So, what does this have to do with your thyroid?

The effect of overt hypothyroidism on cholesterol has been well documented for years. At an American Thyroid Association Symposium, John H. Lazarus, MD said, “There is a huge emphasis on lipid screening, and one cannot assume that all of this is just due to a rise in lipids for no obvious reason—you might be uncovering a thyroid problem. It is very important to appreciate that.”

How does this work? If you have hypothyroidism, your body isn’t making enough thyroid hormones, which can have a pretty major effect on cholesterol levels. In an updated review in the Journal of Clinical Endocrinology and Metabolism, Elizabeth N. Pearce, MD, MSc, professor of medicine at Boston University School of Medicine in Massachusetts, details two major ways low thyroid hormones can lead to high cholesterol.3

First, thyroid hormones help regulate LDL cholesterol clearance. Too little thyroid hormones, translate to less LDL-C receptors on cell surfaces, which translates to not enough cholesterol clearance and an increase in bad cholesterol, LDL. Second, low thyroid hormones may cause greater intestinal cholesterol absorption. The net effect is hyperlipidemia, a big word for high cholesterol.3

A team of scientists at Erasmus University in Rotterdam, Netherlands, led by Arjola Bano, MD, DSc, examined data of 9,420 patients enrolled in the in the Rotterdam Study for nearly nine years, looking at their levels of TSH, free thyroxine (fT4) and risk of heart disease or cerebrovascular disease.4 What they discovered is that as fT4 increases, the risk of developing heart disease is doubled, and there is an 87% greater risk of suffering from an atherosclerosis-related event such as heart attack or stroke.4 Atherosclerosis is a scientific term for heart disease.

According to Dr. Bano, “our findings suggest that thyroid hormone (fT4) measurement can help identify individuals at increased risk of atherosclerosis.”

Treatment Options for High Cholesterol with Hypothyroidism

For information about best treatment options, Dr. Pearce told EndocrineWeb, “In patients with both hypothyroidism and hyperlipidemia, the hypothyroidism should be treated first, and, for patients with optimally treated hypothyroidism who still require treatment for high cholesterol, the options are the same as those for patients with hyperlipidemia but without thyroid disorders.”

Also, it is possible, even more likely, to have overt hypothyroidism and primary hyperlipidemia, in which case both conditions should be treated separately, she said.

Hyperlipidemia can also be a considerable risk for people with subclinical hypothyroidism. While there is less consensus regarding the treatment of high cholesterol in people who have subclinical hypothyroidism, several studies point to possible links.4,5

For example, Gabriela Brenta, MD, an associate professor of endocrinology and biochemistry at Buenos Aires University in Brazil, reports that elevated thyroid stimulating hormone (TSH) levels are associated with an unfavorable lipid profile and suggests the need for thyroid hormone (T4) supplementation as a possible treatment. This research was one of a series of studies making a connection between high TSH levels and elevated blood cholesterol in which a person’s TSH appears directly proportional to blood lipid levels—the higher the TSH, the higher person’s lipids, too.4 The primary factor driving this process is the cholesterol-synthesizing enzyme, HMGCR (3-hydroxy-3-methyl glutaryl-CoA reductase), which is targeted by the statin medications prescribed to lower blood cholesterol levels and reduce the risk of heart disease.

Hypothyroidism and Cholesterol: Should This Matter to Me?

First and foremost, you should discuss your thyroid status and any concerns you have about your cholesterol levels and cardiovascular health with your doctor, if you haven’t already. While the thyroid replacement medication, levothyroxine, is effective in reversing thyroid-related hyperlipidemia in overt hypothyroidism, there is a lack of consensus regarding whether or not to treat hyperlipidemia in patients with subclinical hypothyroidism.

According to Dr. Pearce, “Treatment of subclinical hypothyroidism can be considered in patients with hyperlipidemia, particularly if there are other reasons to treat. For example, the presence ofhypothyroid symptoms. However, there is currently not strong evidence for prescribing thyroid replacement in these patients otherwise.”

Dr. Gabriel Brenta recommends treating with levothyroxine “in those patients with hypercholesterolemia and subclinical hypothyroidism (TSH between 5.5 and 10mU/L) provided they are below 65 years of age.” Her recommendation matches the Clinical Practice Guidelines for Hypothyroidism in Adults Cosponsored by the American Associate of Clinical Endocrinologists and the American Thyroid Association.6 Dr. Brenta and her team also recommend that levothyroxine replacement therapy may be considered for patients with persistently mildly elevated TSH levels and confirmed Hashimoto’s thyroiditis.

Since thyroid hormones levels will affect individuals differently, it is important to talk with your doctor about the treatment options that will best support your health and lifestyle, taking into account all your medical risks, family history, and current thyroid status.

How to Address Your Concerns about Heart Disease with Hypothyroidism

Certainly, the best approach is to be preventative. Here is where exercise can play a major role in helping to promote cardiovascular health. Walking an hour a day is great, and if you are up for something more intense, you might consider adding resistance training or a work-out with weights. Moderate intensity exercises, such as hiking, swimming or Zumba (a form of line dancing) have been shown to increase HDL levels, which will help counteract a higher LDL. The more active you are, and better chance you have to protect your heart and improve your cholesterol profile.

Not ready to jump into weight training? No problem. If hypothyroidism hasn’t been making you feel tired, having high cholesterol also can impair your aerobic capacity, making exercise more difficult. But there’s good news from two population-based cohort studies that measured the benefits of low intensity walking versus moderate exercise.[REFS} Participants in the walking groups were more likely to complete the full 150 minutes of weekly exercise recommended by the Centers for Disease Control and Prevention, and they reported improvements in their physical well-being. The bottom line: Doing some type of physical activity for at least 20-30 minutes every day can advance your heart health.

Remember, knowledge is power. Know your blood cholesterol numbers. Ask your doctor if you should be making any changes to your diet, level of physical activity, or medications, to improve your blood cholesterol. And, as always, keep track of your thyroid levels. If you have any form of hypothyroidism, practice a heart healthy lifestyle that includes staying active, following a heart healthy diet, and taking measures to reduce stress. Managing your hypothyroidism or thyroiditis doesn’t have to stop you from living your best life.

Last updated on 06/21/2018 View Sources

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  2. Bano A, Chaker L, Mattace-Raso F, et al. Thyroid function and the risk of atherosclerotic cardiovascular morbidity and mortality: The Rotterdam Study. Circ Res. 2017;121:1392-1400.
  3. Pearce EN. Update in lipid alterations in subclinical hypothyroidism. J Clin Endocrinol Metab. 2012;97(2):326-33.
  4. Duntas LH, Brenta G. The effect of thyroid disorders on lipid levels and metabolism. Med Clin N Amer. 2012;96(2):269-281.
  5. Razvi S, Jabbar A, Pingitore A, et al. Thyroid hormones and cardiovascular function and diseases. J Amer Coll Cardiol. 2018;71(16):1781-1796.
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What You Need to Know About Cholesterol When You Have Hypothyroidism

Hypothyroidism may lead to high cholesterol, which can increase your risk of heart attack and stroke. Getty Images

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Thyroid problems can have a ripple effect throughout your body, including your cardiovascular system. In particular, people with hypothyroidism may have high levels of LDL (“bad”) cholesterol, which can increase the risk of heart disease. Here’s what you need to know about this potential danger.

What Is Cholesterol?

Cholesterol is a waxy substance your body uses to make hormones and build cells, among other important functions, according to the American Heart Association (AHA). Your liver makes all the cholesterol your body needs, but you can also get cholesterol from foods such as meat and full-fat dairy. There are two types: high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol.

HDL, or “good” cholesterol, carries cholesterol from other parts of your body to your liver, where it’s broken down and removed from the body.

LDL cholesterol is known as “bad” cholesterol because a high level of it in your blood can contribute to a buildup of plaque in your arteries, leading to atherosclerosis. This condition narrows your arteries and can increase your risk of heart attack, stroke, and peripheral artery disease. Currently, about 1 in 3 Americans have high levels of LDL cholesterol, according to the Centers for Disease Control and Prevention.

The High Cholesterol–Hypothyroidism Connection

LDL particles exit your bloodstream through your liver, a process that requires thyroid hormone, says Elizabeth A. McAninch, MD, an assistant professor in endocrinology, diabetes, and metabolism at Rush University in Chicago. If a person has low thyroid hormone levels, or hypothyroidism, it can cause elevated LDL cholesterol levels, she says.

Cholesterol levels are measured through a simple blood test. Ideally, your LDL levels should be less than 100 milligrams per deciliter (mg/dL), according to the Cleveland Clinic; 160 mg/dL or more is considered high. Lipid guidelines from the American College of Cardiology and AHA recommend that people with elevated cholesterol levels be screened for secondary causes, including hypothyroidism, which should be treated, if applicable.

Not only are elevated LDL levels associated with an increased risk of heart attack and stroke, but high cholesterol may also be associated with neurodegenerative disease, such as Alzheimer’s, says Dr. McAninch. “Untreated hypothyroidism has been shown to be associated with increased cardiovascular mortality and morbidity,” she says. “That’s one of the reasons that the American Thyroid Association (ATA) guidelines recommend treating patients with overt hypothyroidism.”

Treating hypothyroidism with thyroid hormone may help to lower cholesterol levels, according to the ATA. But it’s possible that standard treatment alone isn’t quite enough to keep all systems running normally. A research review and meta-analysis by McAninch and her colleagues published in the August 2018 issue of The Journal of Clinical Endocrinology & Metabolism showed that LDL and total cholesterol levels were not fully restored even in people with supposedly adequate treatment of their hypothyroidism. Specifically, LDL and total cholesterol remained higher in people with hypothyroidism who were taking levothyroxine at doses to achieve normal serum thyroid-stimulating hormone levels, she said.

How to Reduce Your Cholesterol Levels

If you have hypothyroidism and high cholesterol, there are steps you can take to lower cholesterol levels and reduce your risk of heart disease. Try these tips.

Lose weight Excess weight contributes to inflammation and metabolic problems, including high cholesterol, according to an April 2014 study published in the International Journal of Molecular Sciences. The good news is that losing even a modest amount of weight can be helpful. “It’s important to know that even a very small change in weight, like 10 pounds, can make an impact on your cholesterol,” says McAninch.

Get regular exercise Exercise can help clear lipids, such as LDL, from your bloodstream, suggests a study published in December 2016 in the Translational Journal of the American College of Sports Medicine. McAninch evaluates her patients’ cardiovascular health and then recommends a tailored exercise plan based on their fitness level. Some people start with slow walking to increase their activity, but others can do high-intensity exercise. “It’s important to find an activity you like and will do,” she says.

Improve your diet A heart-healthy diet rich in fruits and vegetables, whole grains, and lean protein sources like poultry, fish, and nuts, and low in saturated and trans fats, can have a big effect on your cholesterol levels. For example, a review and meta-analysis published in the May–June 2018 issue of Progress in Cardiovascular Diseases suggests that people who followed a diet rich in plant-based, cholesterol-lowering foods such as nuts had LDL cholesterol levels 17 percent lower than those who didn’t follow that diet. Meanwhile, junk foods like fast food, soda, cakes, candies, and cookies may contribute to elevated cholesterol levels. If your diet is packed with these foods, start making small changes you can build on. “It can be daunting to go from a very unhealthy diet to a diet, so I try to just make one or two suggestions to start,” says McAninch. Eliminating soda is a great first step. Trade it for unsweetened bubbly water.

Take cholesterol-lowering medication It might seem obvious, but many people with hypothyroidism may need to add cholesterol-lowering statin drugs to their regimens. A study by McAninch and her colleagues published in October 2016 in The Journal of Clinical Endocrinology and Metabolism found that more people with hypothyroidism were taking significantly more statins.

Another, even larger study by other researchers, published in February 2017 in the journal Thyroid, confirmed that more people with hypothyroidism were taking significantly more cholesterol-lowering drugs. “In both of these studies, it is interesting and important to point out that the patients with hypothyroidism were being treated for their hypothyroidism,” McAninch says.

Take your thyroid medication as prescribed “It’s important for patients with overt hypothyroidism to take thyroid hormone replacement therapy and be monitored regularly by their doctors,” says McAninch. “Hypothyroidism is usually a chronic medical condition and, in my opinion, it’s important for the patient to have a healthcare team to support them while navigating through different life stages, such as growth, development, pregnancy, menopause, and aging, for example.”

BACKGROUND
The risk for developing heart disease is higher in individuals with certain risk factors, which include high cholesterol, high blood pressure, and diabetes. Thyroid hormone has clear effects on the heart and on cholesterol levels. Patients with hyperthyroidism have an increased risk for irregular heart rhythms (atrial fibrillation) while patients with hypothyroidism have higher cholesterol levels. Because of this, there have been several studies suggesting potential associations between mild thyroid problems and heart problems. However, whether mild hypothyroidism or mild hyperthyroidism may be related to cardiovascular disease remains uncertain. This study was done to assess the associations between mild hypothyroidism or mild hyperthyroidism and common risk factors for heart disease such as cholesterol levels, blood pressures, and diabetes and events such as a heart attack and stroke.

THE FULL ARTICLE TITLE:
Martin SS et al. Thyroid Function, Cardiovascular Risk Factors, and Incident Atherosclerotic Cardiovascular Disease: The Atherosclerosis Risk in Communities (ARIC) Study. J Clin Endocrinol Metab. 2017 Jun 12. doi: 10.1210/jc.2017-00986.

SUMMARY OF THE STUDY
The study examined data from the Atherosclerosis Risk in Communities (ARIC) Study, a group of men and women from the general U.S. population without prior known heart attack, stroke, or heart failure. Collected blood drawn in 1990-1992 was measured for thyroid function tests to determine whether individuals had normal thyroid function, hypothyroidism, or hyperthyroidism. If hypothyroidism or hyperthyroidism was found, it was categorized as either mild or moderate/severe.

Thyroid hormone: How it affects your heart

Image: Thinkstock

The thyoid gland, which wraps around the windpipe, releases hormones that have wideranging effects on the body.

Updated: September 17, 2019Published: February, 2015

Too little or too much of this crucial hormone can contribute to heart problems.

Located at the base your throat, the butterfly-shaped thyroid gland releases hormones that affect every organ in your body—especially your heart. Thyroid hormone influences the force and speed of your heartbeat, your blood pressure, and your cholesterol level. As a result, a malfunctioning thyroid gland can cause problems that masquerade as heart disease or make existing heart disease worse.

An estimated 6% of people in the United States have thyroid disease. Most of them—about 80%— have an underactive thyroid, or hypothyroidism. When thyroid levels drop, all the systems in the body slow down, triggering a range of symptoms that include fatigue, weight gain, cold intolerance, constipation, and dry skin. But these symptoms are very common in people as they grow older, including those with normal thyroid levels.

“More than half of people with normal thyroid function have symptoms of hypothyroidism,” says Dr. Jeffrey Garber, an endocrinologist at Harvard-affiliated Beth Israel Deaconess Medical Center and medical editor of the Harvard Special Health Report Thyroid Disease (available at www.health.harvard.edu/TD). In addition, some people over age 60 with low thyroid levels don’t have the classic symptoms. That’s why recognizing hypothyroidism can be particularly tricky, he adds. Certain factors make people more likely to have thyroid problems.

Hypothyroidism: The cardiac connection

Hypothyroidism can affect the heart and circulatory system in a number of ways. Insufficient thyroid hormone slows your heart rate. Because it also makes the arteries less elastic, blood pressure rises in order to circulate blood around the body. Elevated cholesterol levels, which contribute to narrowed, hardened arteries, are another possible consequence of low thyroid levels.

Another noncardiac symptom—muscle aches—may also be relevant. Muscle aches can be a symptom of hypothyroidism as well as a side effect of cholesterol-lowering statin medications, a condition known as statin-related myalgia. In fact, research suggests that hypothyroidism is more common in people who can’t tolerate statins. “Some experts believe that treating hypothyroidism may relieve or decrease statin-related myalgia,” says Dr. Garber.

Hyperthyroidism: Excess thyroid hormone

The opposite problem, hyperthyroidism, or too much thyroid hormone, is far less common, affecting less than 1% of the population. But it, too, can harm the heart.

The classic symptoms include sleeplessness, heat intolerance, excess sweating, weight loss, extreme hunger, and loose bowels. Excess thyroid hormone also causes the heart to beat harder and faster and may trigger abnormal heart rhythms. One is atrial fibrillation, a disorganized rhythm in the heart’s upper chambers. A related symptom is palpitations, a sudden awareness of your heartbeat. People with hyperthyroidism may also have high blood pressure. In a person with clogged, stiff heart arteries, the combination of a forceful heartbeat and elevated blood pressure may lead to chest pain or angina.

Who’s at risk for thyroid problems?

The following factors affect your odds of having a thyroid problem:

  • The following factors affect your odds of having a thyroid problem:

  • Family history. People whose first-degree relatives (parents or siblings) have an underactive or overactive thyroid face a higher risk of a similar problem.
  • Gender. Women are five to eight times more likely to have thyroid problems than men.
  • Age. The prevalence of hypothyroidism rises with age, especially after age 60.
  • Race. Whites have higher rates of hypothyroidism than Hispanic Americans and African Americans.
  • Health history. Thyroid problems are more likely among people with a personal or family history of certain conditions, including type 1 diabetes, Addison’s disease, pernicious anemia, rheumatoid arthritis, premature gray hair, radiation treatments to the head and neck, and vitiligo.

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As a service to our readers, Harvard Health Publishing provides access to our library of archived content. Please note the date of last review on all articles. No content on this site, regardless of date, should ever be used as a substitute for direct medical advice from your doctor or other qualified clinician.

An Association Between Varying Degrees of Hypothyroidism and Hypercholesterolemia in Women: The Thyroid‐Cholesterol Connection

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Effect of Thyroid Dysfunction on High-Density Lipoprotein Subfraction Metabolism: Roles of Hepatic Lipase and Cholesteryl Ester Transfer Protein1

abstract

To investigate the effect of thyroid dysfunction on high-density lipoprotein (HDL) metabolism, we measured HDL subfractions, apolipoprotein A-I containing particles (LpA-I and LpA-I:A-II), and the activities of enzymes involved in the remodeling and metabolism of HDL in 18 hyperthyroid and 17 hypothyroid patients before and after treatment. HDL was subfractionated by density gradient ultracentrifugation, and LpA-I was analyzed by electroimmunodiffusion. The major changes were found in the HDL2 subfraction and in LpA-I particles. HDL2-C and LpA-I were reduced in hyperthyroidism (P < 0.01, P < 0.05, respectively) and increased in hypothyroidism (both P < 0.05) compared with their respective euthyroid matched controls. Changes in HDL2-cholesterol were reversed after treatment in both hyper- and hypothyroid patients, and LpA-I also decreased in the hypothyroid patients after treatment. HL (P < 0.05) and CETP activities (P < 0.05) were elevated in hyperthyroidism and reduced in hypothyroidism (P < 0.05, P < 0.01 respectively) and both were related to free T4 levels. The changes in HDL2-C and LpA-I correlated significantly with changes in HL after treatment but not with CETP or lipoprotein lipase. In summary, HDL metabolism was altered in thyroid dysfunction, and the effect of thyroid hormone on HDL was mediated mainly via its effect on HL activity.

THE EFFECT of thyroid dysfunction on low-density lipoprotein (LDL) metabolism is well described in the literature. Thyroid hormone has been shown to modulate LDL receptor activity, thus leading to changes in plasma LDL levels, which are reversible on treatment of the underlying thyroid disorder. However, the effect of thyroid dysfunction on high-density lipoprotein (HDL) metabolism is less well understood. HDL cholesterol has been reported to be normal (1) or decreased (2, 3) in hyperthyroidism, whereas in hypothyroidism, HDL has been reported to be increased (3–5), normal (6), or even decreased (7). Apolipoprotein (apo) A-I level tends to mirror the changes in HDL cholesterol. Limited information is available on the effects of thyroid dysfunction on the distribution of HDL subfractions and their metabolism. There is only one published study that examined HDL subfractions in hyperthyroidism. Muls et al. (2) reported that the concentration of HDL2b is decreased in hyperthyroid patients. In hypothyroidism, several studies have examined the effect of T4 replacement therapy on HDL subfractions (4, 6, 8, 9). HDL2 decreased after treatment, and the changes in HDL subfractions are thought to be mediated by the effect of thyroid hormone on hepatic lipase (HL) (8).

We have recently shown that plasma cholesteryl ester transfer protein (CETP) is increased in patients with hyperthyroidism and reduced in those with hypothyroidism compared with their respective matched euthyroid controls (10). CETP is a hydrophobic glycoprotein that mediates the transfer of neutral lipids between lipoproteins and plays an important role in the metabolism of HDL and apo A-I and in the reverse cholesterol transport pathway (11). The aim of the present study was to investigate the relative roles of CETP and HL in the metabolism of HDL subfractions in patients with thyroid dysfunction. We had documented HDL subfractions and apo A-I-containing particles (LpA-I and LpA-I:A-II) in the cohort of patients described in our previous study (10), and determined whether the changes in HDL subfractions were related to changes in the activities of plasma lipolytic enzymes and/or CETP.

Patients and Methods

Patients with thyroid dysfunction were recruited from the Thyroid Clinic of the University of Hong Kong. Eighteen female patients with active Graves’ disease and 17 patients (3 males and 14 females) with newly diagnosed hypothyroidism were recruited. The patients’ clinical characteristics were described previously (10). Each patient was matched with a euthyroid control of similar age, sex, and body mass index (BMI). All subjects had fasting blood samples taken for the measurement of lipids, HDL subfractions, apolipoproteins, CETP, free T4 (FT4), and TSH. A second fasting blood sample was taken 15 min after 100 U/kg heparin was administered iv for the measurement of HL and lipoprotein lipase (LPL) activities. The hyperthyroid patients were started on antithyroid drug, and T4 replacement was started in the hypothyroid patients. All parameters were measured again in the both groups of patients after 3–4 months of treatment when they had been rendered euthyroid. All subjects gave their informed consent, and the protocol was approved by the Ethics Committee of the University of Hong Kong.

Methods for measuring plasma lipids and thyroid function were described previously (10). The normal range of FT4 was 10–19 pmol/L, and of TSH was 0.35–5.5 mIU/L. Serum apo A-I and apo B were measured by rate nephelometry using the Beckman Array System (Beckman Instruments, Palo Alto, CA). LpA-I was analyzed by electroimmunodiffusion using commercially available kits (Sebia, Issy les Moulineaus, France). The concentration of LpA-I:A-II was determined by the difference between total serum apo A-I and LpA-I concentrations.

HDL subfractions were isolated by density gradient ultracentrifugation as described by Kelley and Kruski (12) with minor modifications to the density gradient to improve the separation of HDL subfractions. Ultracentrifugation was carried out at 14 C, 38,000 rpm for 24 h in a Beckman SW-40 rotor. The gradient containing the separated HDL fractions was displaced upwards from the tube by infusing a dense, hydrophobic material (Maxidens, 1.9 g/mL, Sigma, CA) under the plasma layer by a constant infusion pump. The elute was passed through a ultraviolet detector and continuously monitored at 280 nm, and fractions were collected for analysis of cholesterol and protein.

Total lipolytic activity in postheparin plasma was measured using an emulsion of triolein and gum arabic as substrate (13). HL activity was determined as the activity of the salt-resistant lipase in the presence of 1 m NaCl. LPL activity was obtained as the difference between total postheparin plasma lipase activity and HL activity (14). Plasma CETP activity was measured as previously described (10).

Data were tested for normality using the Wilk-Shapiro test. FT4 level was logarithmically transformed before analyses were made because of its skewed distribution. The longitudinal analysis of each variable pre- and posttreatment in the patient groups was evaluated by paired t test. Associations between different parameters were determined by Pearson correlation coefficients. The statistical package RS/1 (Bolt Beranek and Newman, Cambridge, MA) was used for data analysis.

Results

Table 1.

Fasting lipid profiles, apolipoproteins, lipolytic enzymes, and CETP in hyperthyroid patients and controls

TC, total cholesterol; TG, triglyceride. Values are means ± sd.

a

Previously published in JCEM 1998;83:140.

b

P < 0.05 compared with controls.

c

P < 0.01 compared with controls.

d

P < 0.01 compared with pretreatment.

e

P < 0.001 compared with pretreatment.

Table 1.

Fasting lipid profiles, apolipoproteins, lipolytic enzymes, and CETP in hyperthyroid patients and controls

TC, total cholesterol; TG, triglyceride. Values are means ± sd.

a

Previously published in JCEM 1998;83:140.

b

P < 0.05 compared with controls.

c

P < 0.01 compared with controls.

d

P < 0.01 compared with pretreatment.

e

P < 0.001 compared with pretreatment.

Table 2.

Fasting lipid profiles, apolipoproteins, lipolytic enzymes, and CETP in hypothyroid patients and controls

TC, total cholesterol; TG, triglycerides. Values are means± sd.

a

Previously published in JCEM 1998;83:140.

b

P < 0.05 compared with controls.

c

P < 0.01 compared with controls.

d

P < 0.05 compared with pretreatment.

e

P < 0.01 compared with pretreatment.

f

P < 0.001 compared with pretreatment.

Table 2.

Fasting lipid profiles, apolipoproteins, lipolytic enzymes, and CETP in hypothyroid patients and controls

TC, total cholesterol; TG, triglycerides. Values are means± sd.

a

Previously published in JCEM 1998;83:140.

b

P < 0.05 compared with controls.

c

P < 0.01 compared with controls.

d

P < 0.05 compared with pretreatment.

e

P < 0.01 compared with pretreatment.

f

P < 0.001 compared with pretreatment.

Hyper- and hypothyroidism appeared to cause reciprocal changes in HL and CETP activities, and baseline HL and CETP activities were both related to log(FT4) when data from the hyper- and hypothyroid patients were combined (HL: r = 0.55, P < 0.001; CETP: r = 0.63, P < 0.001). To determine whether the changes in HDL subfractions and apo A-I-containing particles were related to changes in lipase and CETP activities, correlation analyses were performed. The changes in HDL2-C (ΔHDL2-C) after treatment were related to changes in HL (ΔHL) (Fig. 1) and the changes in BMI (r = 0.45, P < 0.01) but not with CETP or LPL. The relationship between ΔHDL2-C and ΔHL remained significant after controlling for changes in BMI (partial correlation coefficient 0.48, P < 0.01). The changes in HDL3-C after treatment correlated only with ΔHL (r = 0.51, P < 0.01) and not with any of the other parameters including CETP, LPL, and BMI. Changes in LpA-I (ΔLpA-I) also correlated only with ΔHL (Fig. 2).

Figure 1.

Correlation between changes in HL (ΔHL) and changes in HDL2-C (ΔHDL2-C) after treatment in hyper- and hypothyroid patients.

Figure 1.

Correlation between changes in HL (ΔHL) and changes in HDL2-C (ΔHDL2-C) after treatment in hyper- and hypothyroid patients.

Figure 2.

Correlation between changes in HL (ΔHL) and changes in LpA-I (ΔLpA-I) after treatment in hyper- and hypothyroid patients.

Figure 2.

Correlation between changes in HL (ΔHL) and changes in LpA-I (ΔLpA-I) after treatment in hyper- and hypothyroid patients.

Discussion

Thyroid dysfunction has a marked effect on the distribution and composition of HDL particles, and the major HDL subfraction affected appears to be HDL2. The present study showed that HDL2 is reduced in hyperthyroidism and elevated in patients with hypothyroidism, and this is in keeping with the findings of previous studies (2, 8). In addition to classifying HDL particles according to their size and density, HDL particles can also be characterised according to the apolipoprotein composition. Apo A-I and A-II are the major proteins found in HDL and form the two major HDL subclasses: those that contain only apo A-I (LpA-I) and those that contain both apo A-I and apo A-II (LpA-I:A-II). In normal subjects, the relative proportion of LpA-I is greater in HDL2 than in HDL3. There is recent evidence to suggest that the protein composition of HDL significantly affects its antiatherogenic potential, and data from clinical and experimental studies suggest that LpA-I is more antiatherogenic (15). The changes in LpA-I and LpA-I:A-II particles in thyroid disorders have not been studied previously. We showed that LpA-I concentration was lowered in hyperthyroidism and increased in hypothyroidism, whereas LpA-I:A-II concentration was unaffected. The previously well-described changes in plasma apo A-I in hyper- and hypothyroidism are mainly caused by changes in the concentration of LpA-I rather than in LpA-I:A-II particles. This is supported by the findings of O’Brien et al. (5) who reported significant changes in apo A-I concentrations after treatment of hyper- and hypothyroid patients but levels of apo A-II that remained unchanged (5). Whether the increase in LpA-I level in hypothyroidism may partially counteract the harmful effect of raised LDL in hypothyroidism remains to be proven.

Factors that influence HDL lipid composition and therefore size are known to have an important effect in modulating HDL and apo A-I metabolism. HDL particle size appears to be inversely correlated with the rate of apo A-I catabolism, with smaller HDL particles and lipid-poor apo A-I being catabolized more rapidly (16). Because plasma lipoproteins are continuously remodeled during their transit through the plasma compartment by the actions of lipolytic enzymes and lipid transfer proteins, the activities of these proteins are important determinants of the lipid composition and size of HDL and hence its metabolism (17). Changes in postheparin lipase and CETP activities have been described in hyper- and hypothyroidism, and this is the first study to evaluate the relative roles of these enzymes in thyroid hormone-induced changes in HDL subfractions. Because the changes in HDL subfractions after correction of the underlying thyroid disorder correlated mainly with the changes in HL activity, HL appears to be the major factor in determining HDL levels. CETP and LPL appear not to play a significant role. HL is involved in the conversion of HDL2 to HDL3, and transgenic mice and rabbits that overexpress HL have markedly reduced HDL-C and apo A-I (18, 19). Whether the changes in apo A-I observed in our study is because of changes in synthesis and/or because of changes in metabolism remains to be determined. Experimental studies have shown that apo A-I messenger RNA (mRNA) synthesis is reduced in the liver and in the intestine in hypothyroidism, and that thyroid hormone stimulates apo A-I transcription (20, 21). However, plasma apo A-I concentration actually decreased after T4 replacement in our hypothyroid patients. We postulate that because smaller HDL particles and lipid-poor apo-AI are known to be catabolized more rapidly (16, 19), the changes in HL activity might indirectly affect the catabolism of apo A-I through its lipolytic effect on the lipid portion of HDL particles and hence override the effect of thyroid hormone on apo A-I mRNA synthesis.

In the present study, both HL and CETP activities correlated strongly with thyroid hormone levels, suggesting that thyroid hormone has a significant effect on the activities of these proteins, although the underlying mechanisms are not clear. Thyroid hormone regulates the transcription of certain genes. For instance thyroid hormone regulates the expression of LDL receptor at the mRNA level. Staels et al. (20) reported that HL gene expression is relatively resistant to alterations in thyroid status, but whether thyroid hormone affects posttranscriptional regulation of HL activity is not known (20). The effect of thyroid hormone on CETP gene expression has not been studied.

In conclusion, thyroid hormone has multiple effects on lipid metabolism. In addition to its well-known effect on LDL metabolism, the present study has demonstrated that HDL metabolism is also altered in thyroid dysfunction. The effect of thyroid hormone on HDL is mediated mainly via its effect on HL activity.

Acknowledgments

We are grateful to Ms. Betty Chu for her technical assistance.

1 This work was supported by a grant from the Committee on Research and Conference Grants of the University of Hong Kong (CRCG 337/041/0052). 1 Nishitani H , Okamura K , Noguchi S , Inoue K , Morotomi Y , Fujishima M. 1990 Serum lipid levels in thyroid dysfunction with special reference to transient elevation during treatment in hyperthyroid Graves’ disease. Horm Metab Res. 22:490–493. 2 Muls E , Blaton V , Rosseneu M , Lesaffre E , Lamberigts G , de Moor P. 1982 Serum lipids and apolipoproteins A-I, A-II, and B in hyperthyroidism before and after treatment. J Clin Endocrinol Metab. 55:459–464. 3 Friis T , Pedersen LR. 1987 Serum lipids in hyper- and hypothyroidism before and after treatment. Clinica Chimica Acta. 162:155–163. 4 Muls E , Rosseneu M , Blaton V , Lesaffre E , Lamberigts G , de Moor P. 1984 Serum lipids and apolipoproteins A-I, A-II, and B in primary hypothyroidism before and during treatment. Eur J Clin Invest. 14:12–15. 5 O’Brien T , Katz K , Hodge D , Nguyen TT , Kottke BA , Hay ID. 1997 The effect of treatment of hypothyroidism and hyperthyroidism on plasma lipids and apolipoproteins AI, AII and E. Clin Endocrinol (Oxf). 46:17–20. 6 Verdugo C , Perrot L , Ponsin G , Valentin C , Berthezene F. 1987 Time-course of alterations of high density lipoproteins during thyroxine administration to hypothyroid women. Eur J Clin Invest. 17:313–316. 7 Agdeppa D , Macaron C , Mallik T , Schnuda ND. 1979 Plasma high density lipoprotein cholesterol concentration in thyroid disease. J Clin Endocrinol Metab. 49:726–729. 8 Kussi T , Taskinen MR , Nikkila EA. 1988 Lipoproteins, lipolytic enzymes, and hormonal status in hypothyroid women at different levels of substitution. J Clin Endocrinol Metab. 66:61–66. 9 Pazos F , Alvarez JJ , Rubies-Prat J , Varela C , Lasuncion MA. 1995 Long term thyroid replacement therapy and levels of lipoprotein (a) and other lipoproteins. J Clin Endocrinol Metab. 80:562–566. 10 Tan KCB , Shiu SWM , Kung AWC. 1998 Plasma cholesteryl ester transfer protein activity in hyper- and hypothyroidism. J Clin Endocrinol Metab. 83:140–143. 11 Tall AR. 1993 Plasma cholesteryl ester transfer protein. J Lipid Res. 34:1255–1274. 12 Kelley JL , Kruski AW. 1986 Density gradient ultracentrifugation of serum lipoproteins in a swinging bucket rotor. Methods Enzymol. 128:170–181. 13 Ehnholm C , Kuusi T. 1986 Preparation, characterisation, and measurement of hepatic lipase. Methods Enzymol. 129:716–738. 14 Eckel RH , Goldberg IJ , Steiner L , Yost TJ , Paterniti JR. 1988 Plasma lipolytic activity. Relationship to postheparin lipolytic activity and evidence for metabolic regulation. Diabetes. 37:610–615. 15 Fruchart JC , Ailhaud G. 1992 Apolipoprotein A-containing lipoprotein particles: physiological role, quantification, and clinical significance. Clin Chem. 38:793–797. 16 Brinton EA , Eisenberg S , Breslow JL. 1994 Human HDL cholesterol levels are determined by apo A-I fractional catabolic rate, which correlates inversely with estimates of HDL particle size. Arterioscler Thromb. 14:707–720. 17 Clay MA , Newham HH , Forte TM , Barter PJ. 1992 Cholesteryl ester transfer protein and hepatic lipase activity promote shedding of apo A-I from HDL and subsequent formation of discoidal HDL. Biochim Biophys Acta. 1124:52–58. 18 Busch SJ , Barnhart RL , Martin GA , et al. 1994 Human hepatic triglyceride expression reduces high density lipoprotein and aortic cholesterol in cholesterol-fed transgenic mice. J Biol Chem. 269:16376–16382. 19 Fan J , Wang J , Bensadoun A , et al. 1994 Overexpression of hepatic lipase in transgenic rabbits leads to a marked reduction of plasma high density lipoproteins and intermediate density lipoproteins. Proc Natl Acad Sci USA. 91:8724–8728. 20 Staels B , Van Tol A , Chan L , Will H , Verhoeven G , Auwerx J. 1990 Alterations in thyroid status modulates apolipoprotein, hepatic triglyceride lipase, and low density lipoprotein receptor in rats. Endocrinology. 127:1144–1152. 21 Strobl W , Gorder NL , Lee YCL , Gotto AM , Patsch W. 1990 Role of thyroid hormone in apolipoprotein A-I gene expression in rat liver. J Clin Invest. 85:659–667. Copyright © 1998 by The Endocrine Society

Levothyroxine Fails to Normalize Cholesterol Levels in Hypothyroidism

Standard hypothyroidism treatment falls short in normalizing high cholesterol levels, according to a new study, published in The Journal of Clinical Endocrinology & Metabolism.

The standard of care for overt hypothyroidism is levothyroxine at doses that normalize serum thyroid stimulating hormone (TSH) levels. Untreated hypothyroidism is well known to raise cholesterol levels. The results of the new study suggest levothyroxine therapy may not truly be normalizing cholesterol levels in patients who use the drug to replicate adequate thyroid function.

“Our data are consistent with the animal models. We have to re-evaluate our guidelines on the standard of care for hypothyroidism,” said lead author Elizabeth McAninch, MD, assistant professor in the Division of Endocrinology and Metabolism at Rush University Medical Center, Chicago, Illinois.

McAninch and colleagues reviewed studies of overt hypothyroidism in which patients were treated with levothyroxine to normalize serum TSH levels. They searched databases for studies that reported other objective markers of thyroid hormone signaling, including serum low-density lipoprotein (LDL), total cholesterol, sex hormone-binding globulin (SHBG), creatine kinase and/or ferritin levels, as well as cognition, energy expenditure, and/or renal function.

Levothyroxine was administered as monotherapy for overt, primary hypothyroidism among non-pregnant adults with normal serum TSH levels. For studies with LDL, total cholesterol, and SHBG outcomes, data were pooled using random effects meta-analysis.

A total of 99 studies met inclusion criteria, including 65 studies that reported serum cholesterol data. The meta-analysis showed that levothyroxine-treated hypothyroid participants with normal serum TSH levels had 3.31 mg/dL higher serum LDL levels and 9.60 mg/dL higher serum total cholesterol levels vs controls.

In studies that did not concomitantly assess healthy controls, serum LDL levels were 138.3 mg/dL and serum total cholesterol levels were 209.6 mg/dL. A meta-analysis of 2 studies showed no significant difference between SHBG levels of levothyroxine-treated participants and controls.

The researchers concluded that, “In studies that utilized levothyroxine monotherapy at doses that normalized the serum TSH for overt, primary hypothyroidism, not all systemic biological markers of thyroid hormone signaling were normalized, including serum LDL and total cholesterol levels.”

The new study looks “specifically at objective metrics of thyroid hormones,” said McAninch. She noted due to the diversity of the studies, the researchers were not able to make conclusions about markers other than cholesterol. With studies that measured cognition, for example, “they all used different cognitive tests. It was difficult to compare them in a systematic way,” she said.

As many as one-fifth of hypothyroid patients complain of continuing symptoms associated with the condition, such as fatigue, weight gain, and depression, even while they are taking levothyroxine. However, these patients often feel that their residual complaints are being dismissed by their doctors, said McAninch.

“Maybe their subjective complaints are a sign that their thyroid hormone replacement regimen might not be doing the full job of a normally functioning thyroid gland. We should take these common patient remarks and design more research to further explore why this is happening,” she said.

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