Overview  

Tangier disease (TD) is named after an island off the coast of Virginia, United States, where it was first identified in a child.¹ This child had orange tonsils, abnormally low levels of high-density lipoprotein (HDL), and an enlarged liver and spleen.¹ While these symptoms may seem unusual, they can be clearly explained by HDL's vital role in cholesterol transport and removal. 

The importance of HDLs

Cholesterol is hydrophobic, meaning it repels or "hates" water, making it unable to mix with or dissolve in water.² These molecules are essential for maintaining healthy cells as they are key components that provide structure and support to the membranes surrounding the cell itself and organelles such as the nucleus and mitochondria.² 

Additionally, they play vital roles in various metabolic processes, including the production of steroid hormones such as oestrogen and testosterone needed for reproduction and bile acids needed for digestion in the gut.² Since cholesterol is hydrophobic, it is challenging to transport it from the liver, where it is produced, or from the food we consume to our cells. This is because our blood and the cytoplasm of our cells are primarily water. 

To transport cholesterol through the body, it is packaged into structures made of fats and proteins, known as lipoproteins.³ This arrangement allows the water-repelling (hydrophobic) cholesterol to be safely enclosed in the centre. At the same time, the water-attracting (hydrophilic) components, including proteins, face outward, allowing the entire structure to move easily through the watery environment of the bloodstream.⁴ 

There are several lipoproteins, two of the most well-known being LDLs and HDLs.³ LDLs, or low-density lipoproteins, contain a higher proportion of cholesterol and are responsible for transporting cholesterol from the liver to the cells, which are used for building membranes and other functions.⁵ In contrast, HDLs, or high-density lipoproteins, have a higher protein content and perform the opposite role. 

HDLs collect excess cholesterol from the tissues and bloodstream and transport it back to the liver, where it can be processed and removed from the body.⁵ This balance between LDL and HDL is essential for maintaining healthy cholesterol levels and reducing the risk of cardiovascular disease.

What is Tangier disease?  

Tangier disease is a rare genetic disorder identified in approximately 100 individuals worldwide since its discovery in 1961.⁶ It is caused by a mutation (a change) in the ATP-binding cassette subfamily A member 1 (ABCA1) gene. Genes act like instruction manuals for our cells, providing the code to produce specific proteins. When a mutation occurs, it can disrupt the structure or function of the resulting protein. In this case, the ABCA1 protein is essential for the production of HDL as it helps transport the cholesterol needed to form HDL particles.⁷ 

While some HDL comes from our diet, the majority is produced in the liver. When the ABCA1 transporter is not working properly due to a mutation, HDL production is significantly reduced. As a result, cholesterol cannot be efficiently removed from the body's tissues, leading to its buildup and contributing to the symptoms and complications seen in Tangier disease.⁶ 

Importance of diagnosing Tangier disease

As Tangier disease is extremely rare, there is limited data available on the life expectancy of affected individuals.⁶ However, it is important to understand that Tangier disease can lead to serious complications, such as increasing the risk of cardiovascular disease.⁶ These complications can impact overall health and quality of life, making early recognition, regular monitoring, and appropriate management essential to help reduce risks and support long-term well-being.⁶ In this article, we will be exploring the following: 

• The key signs and affected organs in Tangier disease 
• The progression and severity of the disease 
• Considerations of conditions with similar symptoms for differential diagnosis 

Key signs and affected organs 

Tangier disease affects multiple organ systems due to the buildup of cholesterol in various tissues.⁶

Differential diagnosis  

It is important to remember that low HDL levels, enlarged liver, and neurological damage are not exclusive to Tangier disease. These clinical features can also occur in a variety of other inherited and acquired conditions. Recognising the broader range of potential causes is essential for accurate diagnosis. 

Inherited disorders that may present with similar symptoms include:⁶ 

• Abetalipoproteinaemia - Also causes neurological problems 
• Niemann-Pick disease - Leads to enlarged liver and spleen, along with neurological deterioration 
• Charcot-Marie-Tooth disease - Results in neurological decline

In addition to genetic conditions, certain medications are known to contribute to low HDL levels or neuropathy. These include:⁶ 

• Beta-blockers - Can lower HDL levels 
• Benzodiazepines - Long-term use may contribute to nerve damage 
• Anabolic steroids - Can reduce HDL levels 

There are other diseases and conditions that may cause similar clinical features, such as:⁶ 

• Human immunodeficiency virus (HIV) - Associated with low HDL levels 
• Chronic inflammation - Can contribute to an enlarged liver or spleen 

FAQs 

Are HDL and LDL good or bad?

HDL is often referred to as ‘good cholesterol,’ while LDL is known as ‘bad cholesterol. ’  

Is Tangier disease curable? 

There is no current therapy for Tangier disease, but the symptoms can be managed through diet and medications. 

At what age does Tangier’s disease start? 

Symptoms can present at any point in your life.¹³

Do low HDL levels make you tired? 

There is no direct link between HDL levels and feelings of tiredness. However, research has identified a connection between sleep duration and cholesterol levels. A study suggests that men who sleep for eight hours or more may have a lower risk of elevated LDL levels.¹⁴

Summary  

Tangier disease is a rare genetic disorder first identified on Tangier Island in Virginia. It is caused by mutations in the ABCA1 gene, leading to extremely low levels of high-density lipoprotein (HDL). This results in tissue cholesterol buildup, causing key symptoms like orange-coloured tonsils, enlarged liver and spleen, swollen lymph nodes, and peripheral neuropathy. Despite low LDL levels, affected individuals may still face early heart disease. It is essential to recognise these distinctive features to diagnose and manage this disease.