Hypoalphalipoproteinemia

What is Hypoalphalipoproteinemia?

Hypoalphalipoproteinemia, also known as HA, is a condition where levels of high-density lipoprotein cholesterol (HDL-C), commonly known as the “good” cholesterol, are quite low. Modern research identifies HA when HDL-C levels fall below the 10th percentile for people of the same age and gender without any other abnormal characteristics in their lipoproteins (the particles that carry cholesterol in the blood). The US National Cholesterol Education Program provides a guideline that HA is considered when the HDL-C level is less than 40mg/dL.

Metabolic syndrome is a health issue made up of several problems, including low HDL-C (“good” cholesterol), high levels of fats known as triglycerides in the blood, a large waistline, high blood pressure, and high blood sugar levels. When it comes to low HDL cholesterol contributing to metabolic syndrome, the guidelines differ for men and women. A dangerously low level is less than 40mg/dL for men, but for women, it’s less than 50mg/dL.

Familial hypoalphalipoproteinemia, which is inherited from parents and predominantly passed down from one generation to the next, can lead to low levels of alpha-lipoproteins. Due to this, patients have a greater chance of developing heart disease and stroke earlier in life. Low levels of “good” cholesterol are known to be one of the major risk factors for heart disease. Furthermore, heart disease can lead to even more serious conditions such as stroke or heart attack.

What Causes Hypoalphalipoproteinemia?

High-density lipoprotein (HDL) is sometimes known as the “good” cholesterol. There are various conditions, called Hypoalphalipoproteinemia (HA), that can lead to reduced levels of HDL. Most of the time, these conditions are inherited, meaning they are passed down from your parents.

Some inherited causes of reduced HDL include Tangier Disease, familial hypoalphalipoproteinemia–which is caused by a change in the Apolipoprotein A-1 Gene, familial combined hypolipidemia, high activity of the Cholesteryl ester transfer protein, lipoprotein lipase deficiency, and familial lecithin-cholesterol acyltransferase deficiency.

There are also secondary causes that can reduce HDL levels, that is, factors not inherited but caused by other underlying conditions or substances:

Severe infections (sepsis), inflammatory conditions such as systemic lupus erythematosus (an autoimmune disease), rheumatoid arthritis (a long-term autoimmune disorder), and Crohn’s disease (a type of inflammatory bowel disease), monoclonal gammopathies (abnormal proteins in the blood), beta-blockers (medications often used to treat high blood pressure and heart conditions), benzodiazepines (a type of medication typically used for anxiety and sleep problems), and testosterone replacement therapy (typically used to treat low levels of testosterone in males).

Risk Factors and Frequency for Hypoalphalipoproteinemia

The National Center for Health Statistics (NCHS) released a report detailing HDL cholesterol levels among U.S. adults who are 20 years old and above. HDL cholesterol levels below 40 mg/dL were regarded as low. The report indicated a clear difference in HDL cholesterol levels among adults based on their compliance with the 2008 physical activity guidelines established by the U.S. Department of Health and Human Services.

According to these guidelines, sufficient physical activity is defined as at least 150 minutes of moderate-intensity aerobic activity per week, 75 minutes of high-intensity exercise, or a combination of the two. The study found that low HDL cholesterol was more common among adults who did not meet these physical activity guidelines (21.0%) compared to those who did (17.7%).

Overall, 19% of U.S. adults had low HDL cholesterol. If looking specifically at those who did not meet the physical activity guidelines, 35.4% of men and 11.8% of women had low HDL cholesterol. For those who met the activity recommendations, 25.0% of men and 9.1% of women had low HDL cholesterol.

The report also highlighted different rates of low HDL cholesterol based on race and ethnicity among those who aligned with the physical activity guidelines. These statistics were as follows:

Hispanic adults: 20.7%
White adults: 18.1%
Asian adults: 14.4%
Black adults: 12.4%

Signs and Symptoms of Hypoalphalipoproteinemia

Low HDL cholesterol, often referred to as “bad cholesterol,” can result in different symptoms depending on the underlying cause. Here are some typical health issues that a person might have if they already have low HDL cholesterol:

Early atherosclerosis or hardening of the arteries
Coronary heart disease
Peripheral Vascular disease, a circulation disorder affecting blood vessels outside of the heart and brain
Stroke or TIA (Transient Ischemic Attack), sometimes called a mini-stroke
Carotid stenosis, a narrowing of the carotid arteries

The following lifestyle conditions or diseases can also contribute to low HDL cholesterol:

Use of tobacco
An inactive, sedentary lifestyle
Kidney disease
Medications such as beta blockers, thiazides, or benzodiazepines

Some people with low HDL cholesterol, but normal levels of the other forms of cholesterol called LDL-C and triglycerides, might have xanthomas, which are fatty growths under the skin, and early coronary heart disease. Heart failure can also be seen in these patients which includes symptoms like swelling of neck veins, abnormal lung sounds when breathing, an enlarged liver, and ankle swelling. They might also have abnormal heart beats, such as atrial fibrillation.

Individuals with a specific genetic disorder known as familial lecithin: cholesterol acyltransferase (LCAT) deficiency often show changes in their eyes that look like a cloudy cornea, anemia, excessive protein in urine, and could have kidney failure. They usually have small, gray-colored dots all over their cornea, but their vision is usually not affected.

Another variation of the LCAT deficiency is called “fish-eye disease” because the person’s eye appears similar to boiled fish. This name was first used in 1975 for a 61-year-old woman with severe corneal clouding, which was also discovered in her sisters and father.

An illness caused by a defect in the gene known as the ATP-binding cassette transporter A1 (ABCA1) is called Tangier disease. People with this condition often have an orange color inside their mouths due to cholesterol-filled cells. They may also have corneal clouding, an enlarged liver and spleen, as well as nerve damage in the arms and legs. Some might even have early coronary heart disease. There are also certain variant forms of a protein, called ApoA-1, that can cause a condition called amyloidosis if they have mutations.

Testing for Hypoalphalipoproteinemia

If your doctor suspects that you have hypoalphalipoproteinemia – a condition where you have low levels of good cholesterol (HDL) – they will run a series of tests. These can include a comprehensive metabolic profile, a plasma fasting lipid profile, and a plasma ApoA-I level test. ApoA-1 is a protein that helps to form HDL cholesterol. By measuring the level of this protein, doctors can get a better understanding of your HDL cholesterol levels.

There can be many reasons someone might have low HDL levels, such as severe liver failure, having too much fat in their blood (hypertriglyceridemia), or taking certain medications. Your doctor will want to rule out these and other secondary causes before diagnosing hypoalphalipoproteinemia. They will do this by taking a complete medical history and running a comprehensive set of tests, including protein electrophoresis (a test to look at the different types of proteins in your blood), a fasting lipid profile, and a hepatic panel (a series of blood tests that provide information about the state of a patient’s liver).

Your doctor will also review your medication list, as certain medications like beta-blockers (drugs primarily used to treat high blood pressure and heart problems) can cause a decrease in good cholesterol levels.

Once the secondary causes are ruled out, your doctor will measure plasma ApoA-I levels. This is done using a test called immunoassay, which helps to check for genetic reasons of low HDL levels.

Depending on your results, your doctor can determine if the low HDL levels are due to a specific disease. Some diseases related to low HDL-cholesterol levels include Tangier disease, LCAT deficiency, and fish-eye disease. All these conditions can cause abnormal lipid levels, which can affect your HDL cholesterol levels.

Treatment Options for Hypoalphalipoproteinemia

If you have hypoalphalipoproteinemia, your doctor’s goal is to reduce your risk for heart disease and boost your levels of HDL (“good”) cholesterol.

Some of the medicines your doctor might prescribe are called statins, like Atorvastatin or Rosuvastatin. These drugs can raise your HDL cholesterol levels by up to 15%. They block an enzyme involved in cholesterol production in your body, which can help lower your LDL or “bad” cholesterol levels. Additionally, statins can increase the amount of HDL and ApoA-I, another protein that helps remove cholesterol from your body. They can also reduce the amount of triglycerides, a type of fat in your blood, which can lower the breakdown of HDL.

One research study with nearly 7,000 men and women found that taking a statin medication increased their HDL cholesterol levels by an average of 6%. Depending on their starting HDL cholesterol level, their risk for heart disease was reduced by 15% to 45%.

Another class of medicines called fibrates, like Gemfibrozil or Fenofibrate, can also help treat hypoalphalipoproteinemia. These drugs are thought to increase HDL cholesterol by roughly 10%. One study found that after a year on Gemfibrozil, HDL cholesterol increased by 6% and triglycerides decreased by 31% in men with heart disease and low HDL levels.

Niacin is a kind of vitamin, also known as nicotinic acid, that can significantly raise HDL cholesterol in some patients. It works by decreasing fatty acids brought to the liver, which reduces triglyceride and VLDL (another type of “bad” cholesterol) levels. However, even though Niacin can significantly raise HDL cholesterol levels, there is limited evidence to suggest it benefits your heart health.

In addition to medication, lifestyle changes can also help manage hypoalphalipoproteinemia. Quitting smoking can increase your HDL cholesterol levels in just 30 days. Losing weight through diet or exercise can improve your cholesterol levels, and doing both together can improve your cholesterol even more.

Before diagnosing a genetic syndrome as the cause of low levels of HDL (good) cholesterol, it’s crucial to first rule out any secondary causes. This can be achieved by taking a detailed medical history, as this may flag other possible contributing factors. This could include inflammation conditions, a rare kind of blood cell cancer known as monoclonal gammopathies, or the use of certain medicines:

Beta-blockers
Benzodiazepines
Testosterone replacement therapy

A comprehensive cholesterol test can help distinguish whether HDL deficiency stands alone or if there are other hereditary lipid disorders present, such as familial combined hyperlipidemia. Deeper genetic causes of HDL deficiency, like Tangier disease, ApoA-I deficiency, and LCAT deficiency, are typically indicated by decreased HDL levels alongside normal or reduced LDL (bad) cholesterol levels. On the other hand, familial combined hyperlipidemia is characterized by decreased HDL levels and increased LDL levels.

What to expect with Hypoalphalipoproteinemia

A meta-analysis – which is a review of multiple research studies – concluded that the risk of Coronary Heart Disease (CHD), a condition where blood vessels supplying blood to the heart are narrowed or blocked, is inversely related to HDL-C levels. HDL-C is short for High-Density Lipoprotein Cholesterol, often referred to as ‘good cholesterol’ because it carries away cholesterol from blood vessels, reducing the risk of heart disease.

To break it down, this analysis included four major studies: FHS, LRCF CPPT, MRFIT. The common finding from these studies was that a slight increase in good cholesterol levels is linked with lowering the risk of heart disease. Specifically, they found that for each 1 milligram per deciliter (mg/dL) increase in HDL cholesterol, there was a 3% decrease in CHD risk in women and a 2% decrease in men.

The Lipid Research Clinics Prevalence Mortality Follow-up Study (LRCF), which only considered fatal outcomes, found that a 1-mg/dL increase in HDL cholesterol reduced cardiovascular disease death rates by 3.7% in men and 4.7% in women. This clearly underscores the importance of maintaining higher levels of good cholesterol for heart health.

Possible Complications When Diagnosed with Hypoalphalipoproteinemia

Multiple research studies have highlighted the connection between low HDL (good cholesterol) levels and increased risk of coronary heart disease. A groundbreaking study in 1977 set the stage by proving a link between lower HDL cholesterol levels and prevalence of heart disease, even after accounting for the levels of LDL (bad cholesterol) and triglycerides. Its findings have been echoed in multiple research studies around the world.

The Münster Heart Study found that individuals with HDL cholesterol levels below 35 mg/dL were three times more likely to develop coronary artery disease compared to those with higher HDL levels. A similar link was found in a study among Asian populations, which suggested a 67% increase in heart events for people with low HDL cholesterol compared to those with normal lipid levels.

In addition, an 8-year follow-up in the Framingham Heart Study revealed that individuals in the 80th percentile of HDL cholesterol had half the risk of developing coronary heart disease compared to those in the 20th percentile. A meta-analysis in 1989 also found a significant decrease in heart disease risk for each 1 mg/dL increase in HDL cholesterol – 2% in men and 3% in women.

But the story doesn’t end with heart disease. A 2022 study found that low HDL levels are also linked to various types of cancer. For example, genes associated with low HDL were found to be prevalent in several types of cancer, such as leukemia, bladder cancer, ovarian cancer, and even breast cancer.

Common Gene Variants:

ABCA1 – Chronic myelogenous leukemia
Stab1 – Bladder cancer and Acute Myelogenous Leukemia
OSBPL1A
CPS1 – Hepatocellular carcinoma (liver cancer)
CD36 – Ovarian cancer
LRP1
ABCA8 – Hepatocellular carcinoma (liver cancer)
GOT2
AMPD3 – Gastrointestinal stromal tumors and lung cancers
WWOX
IRS1 – Medulloblastoma, breast cancer, and osteosarcoma

Lastly, a study involving a large population showed that tumor growth tends to increase with lower HDL levels. Fortunately, by raising HDL levels, it’s possible to lower both cardiovascular and cancer risk.

Preventing Hypoalphalipoproteinemia

Having low levels of good cholesterol due to genetic reasons, a condition known as hypoalphalipoproteinemia, can’t be stopped. However, in some cases, genetic screenings can be done to detect it.

When hypoalphalipoproteinemia occurs due to other causes, it can be managed by addressing the root cause. Things like quitting smoking, mastering a balanced diet, and maintaining a regular exercise routine can help boost the levels of good cholesterol in your body.

Frequently asked questions

Hypoalphalipoproteinemia is a condition where levels of high-density lipoprotein cholesterol (HDL-C), commonly known as the "good" cholesterol, are quite low.

Hypoalphalipoproteinemia is common in 19% of U.S. adults.

Signs and symptoms of Hypoalphalipoproteinemia, also known as low HDL cholesterol or "bad cholesterol," can vary depending on the underlying cause. Here are some typical health issues that a person might experience if they have low HDL cholesterol: - Early atherosclerosis or hardening of the arteries - Coronary heart disease - Peripheral Vascular disease, a circulation disorder affecting blood vessels outside of the heart and brain - Stroke or TIA (Transient Ischemic Attack), sometimes called a mini-stroke - Carotid stenosis, a narrowing of the carotid arteries In addition to these conditions, there are certain lifestyle conditions or diseases that can contribute to low HDL cholesterol, including: - Use of tobacco - An inactive, sedentary lifestyle - Kidney disease - Medications such as beta blockers, thiazides, or benzodiazepines Some individuals with low HDL cholesterol, but normal levels of LDL-C and triglycerides, may also experience specific symptoms such as: - Xanthomas, which are fatty growths under the skin - Early coronary heart disease - Heart failure, with symptoms like swelling of neck veins, abnormal lung sounds when breathing, an enlarged liver, and ankle swelling - Abnormal heart beats, such as atrial fibrillation There are also specific genetic disorders associated with low HDL cholesterol. For example, individuals with familial lecithin: cholesterol acyltransferase (LCAT) deficiency may exhibit changes in their eyes, including a cloudy cornea, anemia, excessive protein in urine, and potential kidney failure. They may also have small, gray-colored dots all over their cornea, although their vision is usually not affected. Another genetic disorder, Tangier disease, caused by a defect in the ATP-binding cassette transporter A1 (ABCA1) gene, can present with symptoms such as an orange color inside the mouth due to cholesterol-filled cells, corneal clouding, an enlarged liver and spleen, nerve damage in the arms and legs, and even early coronary heart disease. In some cases, certain variant forms of a protein called ApoA-1 can cause a condition called amyloidosis if they have mutations. It's important to note that these symptoms and conditions are associated with low HDL cholesterol, but a proper diagnosis and evaluation by a healthcare professional is necessary for accurate assessment and treatment.

Hypoalphalipoproteinemia can be inherited, meaning it is passed down from your parents.

The doctor needs to rule out the following conditions when diagnosing Hypoalphalipoproteinemia: - Severe liver failure - Hypertriglyceridemia (having too much fat in the blood) - Certain medications, such as beta-blockers, benzodiazepines, and testosterone replacement therapy - Inflammation conditions - Monoclonal gammopathies (a rare kind of blood cell cancer)

The tests needed for Hypoalphalipoproteinemia include: - Comprehensive metabolic profile - Plasma fasting lipid profile - Plasma ApoA-I level test - Protein electrophoresis - Fasting lipid profile - Hepatic panel - Immunoassay to measure plasma ApoA-I levels

Hypoalphalipoproteinemia can be treated through a combination of medication and lifestyle changes. Medications such as statins, fibrates, and niacin can be prescribed to raise HDL cholesterol levels and lower LDL cholesterol levels. Statins can increase HDL cholesterol levels by up to 15% and reduce the risk of heart disease by 15% to 45%. Fibrates can increase HDL cholesterol by roughly 10% and decrease triglycerides. Niacin can significantly raise HDL cholesterol levels, but its benefits for heart health are limited. In addition to medication, lifestyle changes like quitting smoking and losing weight through diet and exercise can also help manage hypoalphalipoproteinemia.

When treating Hypoalphalipoproteinemia, there can be side effects associated with the medications prescribed. The specific side effects may vary depending on the medication, but some potential side effects of the commonly prescribed medications include: - Statins (such as Atorvastatin or Rosuvastatin): These drugs can cause muscle pain or weakness, liver damage, and digestive issues like nausea, diarrhea, or constipation. - Fibrates (such as Gemfibrozil or Fenofibrate): Side effects may include stomach upset, gallstones, liver problems, and muscle pain. - Niacin: Niacin can cause flushing, itching, and a feeling of warmth, especially in the face and neck. It can also cause stomach upset, liver damage, and high blood sugar levels. It's important to discuss potential side effects with your doctor and report any concerning symptoms while taking these medications.

Patients with Hypoalphalipoproteinemia (HA) have a greater chance of developing heart disease and stroke earlier in life due to low levels of "good" cholesterol. Low levels of HDL cholesterol are known to be one of the major risk factors for heart disease. Heart disease can lead to even more serious conditions such as stroke or heart attack.

You should see a doctor specializing in cardiology or lipidology for Hypoalphalipoproteinemia.