Dysbetalipoproteinemia

What is Dysbetalipoproteinemia?

“Dysbetalipoproteinemia, also known as familial dysbetalipoproteinemia (FD), hyperlipoproteinemia type III, or broad β disease, is a genetic disorder linked to a buildup of specific fats, called triglyceride-rich remnant lipoproteins, in the body. This accumulation happens because the body isn’t efficiently clearing these fats. Most people with this condition have a specific gene called the apolipoprotein E2 (APOE). Additionally, FD often happens when the apolipoprotein E doesn’t properly attach to the LDL (bad cholesterol) receptors in the body.

Though FD is usually passed down when both parents carry the condition (autosomal recessive), 10% of the cases are due to dominant mutations (only one parent carries the condition). This abnormal metabolism of fats can lead to a buildup of fatty deposits in the arteries, increased levels of serum triglycerides and total cholesterol, and yellowish patches on the palms called palmar xanthomas. FD can lead to serious complications like heart and peripheral vascular disease. Importantly, those with FD are at a ten times higher risk of developing heart disease early compared to the general population.

To diagnose this condition, doctors need to identify the dysbetalipoproteinemia condition and the APOE gene, which are the main causes. Management of FD typically involves a low-fat diet and medications such as statins and fibrates. During treatment, doctors will monitor patients using specific cholesterol testing (non–HDL-C testing) to ensure harmful fats are under control.”

What Causes Dysbetalipoproteinemia?

Familial dysbetalipoproteinemia (FD) is a condition that happens when a person’s apolipoprotein E (APOE) gene changes, leading to Apo E2/E2 homozygotes. The APOE gene usually forms APOE3, but for people with FD, it produces a slightly different version called APOE2. This version is different in just one area, at position 158, where there’s an amino acid substitution – cysteine is in place of arginine.

FD mainly results in an excess of remnant lipoprotein, a type of fat (lipid). ApoE is found in fat-rich particles like chylomicrons, very low-density lipoproteins (VLDL), and intermediate-density lipoproteins (IDL). This protein helps break down these particles by attaching to receptors in the liver. But if a person has the APOE2 version of the gene, the process of connecting these fat-rich particles to receptors in the body is impaired.

There’s a particular receptor, heparan sulfate proteoglycans (HSPG), which is vital for this process. It consists of a long protein strand that sugar polymers attach to. These receptors help capture the fat particles. A specific variant of these HSPG receptors, called syndecan 1 HSPG-R, plays a crucial role in clearing this fat from the body.

Because the APOE2 version of the gene affects how well these particles bind to receptors, harmful fat particles aren’t removed from the body as effectively. This leads to a build-up of these particles in the blood, ultimately increasing the risk of developing atherosclerosis, a disease where plaque builds up in the arteries.

Risk Factors and Frequency for Dysbetalipoproteinemia

The APOE gene has three main versions: E2, E3, and E4. From these three variants, we get six possible combinations. Most people have the E3E3 type. The E2/E2 type is found in most people with visibly higher fat (triglyceride) and cholesterol levels. However, other rare combinations can also lead to this presentation. Mutations in this gene can be passed down either recessively (most common) or dominantly (about 10% of cases).

• Most common type of APOE gene is E3E3
• E2/E2 type is often associated with high fat and cholesterol levels
• There are both common and rare gene combinations that can increase these levels
• Most gene mutations are recessive, but some are dominant

The condition linked to these gene types, dysbetalipoproteinemia, tends to be more prevalent in men and postmenopausal women. Different studies using different definitions have resulted in varying estimates of how common this condition is, ranging from 0.1% to 2.7% of the population. Diagnosis typically involves checking cholesterol levels and identifying the gene types. Phenotypic presentation (visible changes in fat and cholesterol levels) often requires both a genetic predisposition and the influence of environmental factors.

• Dysbetalipoproteinemia often affects men and postmenopausal women
• The condition’s prevalence varies from 0.1% to 2.7% depending on the study
• Diagnosis usually involves checking cholesterol levels and identifying the gene type
• Visible signs often require both genetic and environmental influences

The E2/E2 type can cause lipid imbalance, but only when paired with another genetic or acquired defect. These include factors such as reduced clearance of fat remnants, decreased activity of the LDL receptor (which helps get rid of bad cholesterol) and increased production of VLDL (a type of bad cholesterol).

Another influencing factor is estrogen, a hormone that is more abundant in women before menopause. Estrogen can protect against dysbetalipoproteinemia by affecting the breakdown of fat remnants and the expression of LDL receptors. Consequently, men and postmenopausal women don’t have this protective effect and are more prone to developing the condition.

• The E2/E2 type of APOE gene can result in lipid imbalance when paired with other defects
• These defects could include reduced fat clearance, decreased LDL receptor activity, and increased VLDL production
• Estrogen can protect against dysbetalipoproteinemia by influencing the breakdown of fat remnants and LDL receptor expression
• Men and postmenopausal women, who have less estrogen, are therefore more susceptible to the condition

Signs and Symptoms of Dysbetalipoproteinemia

Dysbetalipoproteinemia is a condition that can present in many different ways. Around half of all patients might develop skin conditions known as xanthomas, which are cholesterol deposits. The most common types of these are eruptive xanthomas or palmar crease xanthomas. Other types like tuberous xanthomas, tendon xanthomas, and xanthelasma are common in various mixed familial lipid disorders but aren’t specific to this particular condition. Palmar and tuberous xanthomas are usually seen when cholesterol levels exceed 1000. Over time, with treatment, palmar crease xanthomas tend to fade away. Sometimes, the first symptoms a patient notices are linked to premature blockages in the arteries, like angina or acute coronary syndrome, or inflammation of the pancreas due to high triglyceride levels.

An interesting study of 305 European patients found that heart and artery diseases are quite common in individuals with familial dysbetalipoproteinemia. The most common types are peripheral artery disease (PAD) and coronary artery disease (CAD), and it’s also common to see insulin resistance and obesity in these patients.

The symptoms patients with dysbetalipoproteinemia and secondary CAD tend to display are the same as for most people with CAD. The most common symptom patients experience is chest pain, whether they’re exercising or at rest. Other, less common symptoms can include feeling tired, shortness of breath when exercising, swelling in the limbs (peripheral edema), and occasional chest discomfort. Peripheral artery disease in these patients might develop without noticeable symptoms, or it might cause specific problems like intermittent claudication (leg pain when exercising), acute limb ischemia (sudden decrease in leg blood flow), or chronic limb ischemia (persistent poor blood supply to the limbs).

To summarize, symptoms can include:

• Skin conditions (xanthomas)
• Cholesterol deposits
• Signs of artery blockages
• Angina
• Acute coronary syndrome
• Inflammation of the pancreas
• Peripheral artery disease
• Coronary artery disease
• Insulin resistance
• Obesity
• Chest pain
• Fatigue
• Shortness of breath when exercising
• Swelling in limbs
• Occasional chest discomfort
• Leg pain when exercising
• Sudden decrease in leg blood flow
• Persistent poor blood supply to limbs

Testing for Dysbetalipoproteinemia

To confirm the presence of dysbetalipoproteinemia, a condition characterized by abnormal fat and cholesterol levels in the bloodstream, doctors need to evaluate both its phenotype (outward features) and the genotype (genetic makeup) involving the APOE gene.

Early indicators might include certain physical signs such as palmar xanthomas (yellowish patches or bumps on the skin) and tuberous xanthomas (firm, painless, reddish-yellow bumps on the skin). A fasting lipid profile could show increased total cholesterol and triglyceride levels, generally between 300 and 1000 mg/dL, pointing towards this condition. However, distinguishing dysbetalipoproteinemia from other APOE genotype abnormalities causing abnormal lipid levels, like familial hypercholesterolemia or hypertriglyceridemia, requires more than just lipid studies.

To confirm the diagnosis, they often carry out genotyping with an evaluation of the APOE gene. In particular, having the E2/E2 genotype is a common indicator but sometimes when the disease is inherited, full APOE sequencing may be necessary.

In addition to genotyping, ultracentrifugation and polyacrylamide gradient gel electrophoresis (PGGE) are commonly used to identify the dysbetalipoproteinemia phenotype. If these methods are not available, apoB testing can be used.

Ultracentrifugation focuses on the following ratios:

• VLDL-cholesterol/VLDL-triglyceride (TG): >0.97
• VLDL-cholesterol/total plasma TG: >0.69

Also, the following measures and thresholds may be indicative of dysbetalipoproteinemia:

• Apolipoprotein B (ApoB)/Total cholesterol ratio: <0.15 g/mmol
• Non-HDL-C/ApoB ratio: >4.91 mmol/g
• ApoB level: <1.2 g/l
• Triglyceride level: at least 1.5 mmol/l
• Triglyceride/ApoB: <10 mmol/g
• Total cholesterol/ApoB: at least 6.2 mmol/g

PGGE methods rely on:

• Small VLDL and intermediate-density lipoprotein (IDL) quantity with little to no LDL
• IDL-range/LDL-range ratio: >0.5

β quantification is another useful test that picks up “β-VLDL” after ultracentrifugation and checks if the VLDL to triglyceride ratio is high – both being characteristics of dysbetalipoproteinemia.

However, these specialist tests aren’t widely available and can’t always be used in all patients with mixed hyperlipidemia. Using the apoB value in comparison to total or non-HDL cholesterol, or within a multi-step algorithm initially to decide on further evaluation, could be a promising approach. With a more comprehensive implementation of diagnostic pathways using Apo B, there could be more effective use of specialized tests and consistent detection of patients with dysbetalipoproteinemia. Therefore, if a steady and evidence-based method to diagnosing dysbetalipoproteinemia is not used, it’s likely many cases will remain undiagnosed.

Treatment Options for Dysbetalipoproteinemia

Managing dysbetalipoproteinemia, a lipid (fat) disorder, involves a combination of lifestyle modifications and medication. Key among these changes is altering the patient’s diet, which can significantly help those with this condition.

Changes in lifestyle include adopting a diet made up primarily of minimally processed, high-fiber, plant-based foods like vegetables, whole grains, legumes, and nuts. This diet has been found to improve hyperlipidemia (high levels of fat in the blood) in most patients. These dietary changes should cut down on saturated fat intake and instead focus on consuming unsaturated fats and long-chain polyunsaturated fatty acids. Introducing more lean proteins, vinegar, fish oil, tea, and cinnamon, and cutting down on alcohol and overall daily calories can also be beneficial. Weight loss and increased daily exercise are recommended as they can help lower triglyceride (a type of fat) levels.

A low-carbohydrate diet is also advised. People with dysbetalipoproteinemia often struggle with insulin resistance, and a diet low in carbohydrates can help lower plasma lipid (fat in the blood) levels. Attention should also be given to risk factors like hypothyroidism, type 2 diabetes, and metabolic syndrome as managing these conditions may help improve triglyceride levels.

If merely changing diet is not enough to maintain healthy lipid levels, a combination of statins and fibrates, medications to reduce cholesterol, is typically recommended. These drugs have been shown to improve LDL (bad cholesterol) levels. It’s important to remember that the goal should not only be to lower LDL cholesterol, which tends to be low in patients with dysbetalipoproteinemia, but also to focus on non-HDL cholesterol. Using statins alone may leave patients with high cholesterol, but incorporating fibrates can improve lipid profiles.

There’s limited data from clinical trials on the effect of lipid-lowering medications in people with familial dysbetalipoproteinemia. These trials generally show a reduction in LDL and total cholesterol levels, but reaching target lipid levels remains uncertain. PCSK9 inhibitors, another class of cholesterol-lowering medication, could potentially be useful for patients who don’t respond to or can’t tolerate statin or fibrate therapy. However, their role in managing familial dysbetalipoproteinemia is still not fully clear.

What else can Dysbetalipoproteinemia be?

When doctors are trying to diagnose dysbetalipoproteinemia, they need to consider several other conditions that could be the cause of similar symptoms, such as high cholesterol and xanthomas (fatty bumps under the skin). These other possibilities include:

• Combined hyperlipidemia: A condition where levels of a fat protein called ApoB are unusually high, leading to an increase in both LDL (bad cholesterol) and VLDL (very low-density lipoprotein, another type of bad cholesterol). This differs from dysbetalipoproteinemia, which does not involve an increase in LDL-C (low-density lipoprotein cholesterol).
• Nephrotic syndrome: A kidney disorder that increases the production of all types of cholesterol.
• Hepatic lipase deficiency: This deficiency affects the conversion of IDL (intermediate-density lipoprotein) to LDL. It also typically leads to high levels of HDL (good cholesterol), presenting similar symptoms to dysbetalipoproteinemia.
• Polygenic hypercholesterolemia, metabolic syndrome, LPL deficiency, hypothyroidism, and familial hypertriglyceridemia: These are all conditions that could cause similar symptoms.

Additionally, it’s important to note that dysbetalipoproteinemia can sometimes be confused with familial hypercholesterolemia, a genetic disorder that can lead to high LDL cholesterol due to defective LDL receptors. In such cases, the LDL cholesterol levels can sometimes appear falsely elevated due to the way it’s calculated using the Friedewald’s formula. This could lead to underestimation of cholesterol in VLDL and overestimation of cholesterol in LDL. Therefore, it’s crucial to also evaluate the causes of xanthomas and xanthelasmas (yellowish patches on the skin or inside the eyelids).

What to expect with Dysbetalipoproteinemia

Patients who receive treatment for familial dysbetalipoproteinemia often experience a positive outlook. Most respond favorably to changes in lifestyle and medical care. However, people with higher levels of triglyceride and total cholesterol are more prone to complications than those without elevated levels. The chances of living a longer, healthier life are more favorable when the condition is diagnosed and treated early.

Dysbetalipoproteinemia is characterized by high amounts of remnant cholesterol. Excessive remnant cholesterol is directly connected to a higher risk of ischemic heart disease and is also tied to an increased risk of overall mortality.

Possible Complications When Diagnosed with Dysbetalipoproteinemia

Dysbetalipoproteinemia is a medical condition that can lead to several complications. More often, these may include:

• Peripheral vascular disease (condition of the blood vessels outside your heart)
• Coronary artery disease (blockage of heart vessels)
• Insulin resistance (a condition where the body does not respond to insulin properly)
• Acute pancreatitis (sudden inflammation of the pancreas)

Besides, people with dysbetalipoproteinemia are often more prone to getting atherosclerosis, a condition where arteries harden. Thus, an early diagnosis and treatment are vital to control these complications.

Preventing Dysbetalipoproteinemia

It’s crucial for anyone diagnosed with dysbetalipoproteinemia to make lifestyle changes, including improving their diet with the help of a professional dietician. Early medical check-ups can catch symptoms quickly and handle any complications. Many patients may not realize that triglyceride levels, along with cholesterol, are important to monitor.

Patients should be aware of the potential complications tied to dysbetalipoproteinemia, particularly the increased risk of heart disease. The good news is that this condition often responds well to simple changes such as balanced diet, regular exercise, and weight loss

A dietitian can provide in-depth dietary advice, while some guidance on exercise can also help treat the condition and decrease the chance of developing heart disease. Also, patients should be informed about the importance of limiting alcohol consumption to no more than one drink per day.

Doctors should also guide patients on how to properly use medications. If a patient also has diabetes, they should be given extensive education about managing their diabetes along with their dysbetalipoproteinemia.