Introduction

Tangier disease is a rare genetic disorder affecting cholesterol transport, with approximately 100 cases identified worldwide. It is inherited in an autosomal recessive manner, meaning an individual must inherit a mutated copy of the gene from both parents to develop the disease. However, people can be carriers of the gene when they inherit one copy from a parent. Tangier disease is characterised by very low levels of high-density lipoprotein (HDL), often referred to as “good cholesterol”.¹

What is HDL, and why does it matter?

HDL stands for ‘high-density lipoproteins’. Lipoproteins are small, round particles made from a combination of lipids (another name for fats) and proteins. These act as carriers to enable the transport of insoluble fats like cholesterol through our bloodstream, where our body needs them. 

Cholesterol is an essential building block in making cell membranes, as well as producing key hormones and helping your body digest food. Two types of lipoproteins carry cholesterol through the blood vessels:

1. High-density lipoproteins (HDL)
2. Low-density lipoproteins (LDL)

HDL carries approximately one-fourth of cholesterol in our body and is very dense, due to a high protein-to-fat ratio. HDL cholesterol is often referred to as “good cholesterol” as it is responsible for removing excess fat from blood vessels and transporting it to the liver for recycling or disposal. This process is known as reverse cholesterol transport, and it is important for maintaining good heart health by protecting your heart and blood vessels from disease.

Other roles of HDL include:

• Anti-oxidant effects: helping to protect cells and important molecules in the blood and tissues from damage
• Anti-inflammatory effects: helping to protect artery walls against blockages

In our body, we also have low-density lipoproteins (LDL). In contrast to HDL cholesterol, LDL cholesterol is often known as “bad cholesterol” because excess LDL cholesterol can accumulate in the arteries (blood vessels that supply organs with oxygenated blood). Circulating LDL can damage artery walls through inflammation. Therefore, maintaining lower levels supports better cardiovascular (heart) health by reducing blood pressure and lowering the risk of heart disease.^2,3,4

Tangier disease and its impact on cholesterol

Tangier disease is a very rare condition which causes a complete absence or an extreme deficiency of HDL cholesterol. Tangier disease develops in the presence of a mutation in the gene ATP-binding cassette transporter A1 (ABCA1). ABCA1 is responsible for providing instructions to make proteins used for making HDL that allow cholesterol to be released from cells and transported to the liver. Mutations in the ABCA1 gene prevent this release of cholesterol from cells, leading to its harmful accumulation.⁵

A buildup of cholesterol can be toxic to cells, leading to abnormal cell function or cell death. Certain body tissues may become enlarged by a buildup of cholesterol, such as the liver, spleen, lymph nodes and most notably, the tonsils, which can also appear yellow/orange. 

Furthermore, the inability to transport cholesterol out of cells leads to very low HDL cholesterol levels in the bloodstream. The lack of cholesterol clearance increases the risk of cardiovascular disease in people with Tangier disease.⁶

Increased cardiovascular risks in Tangier disease

Atherosclerosis: the silent killer

Patients with Tangier disease can develop atherosclerosis, which is an accumulation of fatty material called atheroma (or plaque) in our artery walls. Atheroma is composed of:

• Cholesterol and other fats
• Blood cells
• Protein granules
• Inflammatory immune cells
• Calcium (responsible for hardening the atheroma)

Due to the fact that atheroma builds up over time, many people do not experience symptoms at first. In individuals with Tangier disease, reduced HDL cholesterol levels lead to a faster buildup of plaque in the arteries because of the reduced transport of cholesterol from peripheral tissues back to the liver. The subsequent buildup causes the walls of your arteries to harden and narrow, restricting your blood flow.

Without HDL to remove excess cholesterol, fatty deposits clog arteries and cause complications, depending on the type of artery that is blocked. For example, peripheral artery disease occurs when atheroma causes narrowing of the peripheral arteries (supplying blood to the limbs), limiting the blood flow to the legs and resulting in pain and circulation problems. Other examples include:^1,7,8,9

• Coronary artery disease (CAD): arteries supplying blood to the heart
• Carotid artery disease: arteries supplying blood to the brain

Coronary heart disease

Narrow, stiff arteries can lead to hypertension (high blood pressure). The increased resistance of blood flow means the heart must work harder to pump blood around the body to deliver oxygen and nutrients, resulting in coronary heart disease (CHD). Over time, this can weaken your heart, and it may not be able to pump blood sufficiently for healthy functioning, known as heart failure. 

In Tangier disease, homozygous individuals (who have two copies of the defective gene) have an increased risk of developing premature CHD in their 50s and 60s, but not at an earlier age, as their LDL (bad) cholesterol levels are 50% of normal, offering some protective qualities.¹⁰

Acute cardiac events 

Plaques formed due to atherosclerosis are usually unstable and prone to rupture (breaking). This can trigger the formation of blood clots (thrombosis) around this as an attempt to repair the damage to the artery wall. As a result, individuals with Tangier disease have a higher chance of experiencing acute (sudden) cardiovascular illness, such as heart attacks and strokes.⁵

Heart attacks

Approximately 30% of Tangier disease cases experience premature heart attacks (myocardial infarction). If a thrombosis develops and completely blocks a coronary artery, the heart muscle can not receive any oxygen from the blood supply, leading to a heart attack. Heart attacks can be potentially fatal; thus, if you think you are having a heart attack, call emergency services immediately.⁵ 

Strokes

Carotid artery disease can lead to stroke. Blocked arteries supplying blood to the brain can lead to ischemic strokes, which occur when the blood supply to brain tissue is cut off. When the brain is deprived of essential oxygen and nutrients, brain cells become damaged or die. 

Stroke is a serious medical emergency which can lead to permanent brain damage or death. Reduced HDL cholesterol levels increase the risk of ischemic strokes in patients with Tangier.¹¹

Impaired blood vessel function

HDL is not just about cholesterol clearance, but also about easing inflammation and stimulating nitric oxide production. Nitric oxide promotes vasodilation, which refers to the widening and relaxation of blood vessels. Vasodilation is essential for blood to flow easily through the body, and therefore lowers blood pressure. 

Improved circulation of blood promotes oxygen and nutrient delivery to tissues in the body and facilitates the removal of waste products, supporting cholesterol clearance and reducing fatty deposits in arteries. 

Therefore, HDL dysfunction in Tangier disease may lead to increased inflammation and stiffening of arteries, making blood flow more difficult and increasing the risk of high blood pressure, atherosclerosis and associated heart disease.¹²

Can anything be done?

Currently, there is no cure for Tangier disease. Treatments for patients focus on minimising the symptoms and reducing the chance of cardiovascular health problems. Lifestyle changes, such as eating a healthy diet and exercising, can help manage an individual’s overall cholesterol balance.

Statins are drugs that lower LDL cholesterol in the blood by reducing its production in the liver. These may be useful tools in mitigating cardiovascular health risks, though more research is needed into their effectiveness in Tangier disease.

Individuals with an affected parent should utilise genetic testing to find out if they have inherited any copies of the faulty ABCA1 gene. Furthermore, routine blood tests and blood pressure monitoring should be done to detect potential issues and implement early treatments.

Summary

Although an extremely rare condition, an extreme deficiency of HDL cholesterol in Tangier disease poses serious cardiovascular risks over time, such as blood vessel damage, atherosclerosis and coronary heart disease. Additionally, a long-term accumulation of fatty plaques in blood vessels can elevate the risk of serious acute events, such as a heart attack and stroke. Those affected by Tangier disease must be aware of the risks and implement necessary lifestyle strategies for cholesterol management to reduce complications. Further research into the underlying mechanisms of cholesterol transport can provide useful information on potential treatments for Tangier disease, whilst helping us to understand shared mechanisms in more common causes of heart disease, and to maintain good heart health.