Familial Dysbetalipoprotinemia - Symptoms, Diagnosis and Management

Introduction

Familial dysbetalipoproteinemia is a condition with abnormality in a particular gene, leading to increased triglycerides and total cholesterol levels. In addition, this disease is associated with certain complications, such as peripheral vascular disease and coronary artery disease. Familial dysbetalipoproteinemia (FD), or type III hyperlipoproteinemia according to Fredrickson-Levy-Lees classification, is a genetic disorder in which there is an increased accumulation of triglyceride-rich remnant lipoproteins. It is also associated with an increased risk for premature atherosclerotic cardiovascular disease. Familial dysbetalipoproteinemia also causes an increased risk for premature coronary artery disease.

What Causes Familial Dysbetalipoproteinemia?

A genetic defect causes familial dysbetalipoproteinemia. This defect results in the accumulation of large lipoproteins (particles made up of fats and proteins) that contain triglycerides (a type of fat found in the body) and cholesterol. The disease is linked to defects in the APOE gene (apolipoprotein E). Conditions such as diabetes, obesity, and hypothyroidism can make it worse. The risk factors include a family history of the disorders and coronary artery disease.

What Are the Symptoms of Familial Dysbetalipoproteinemia?

The symptoms of familial dysbetalipoproteinemia are usually not seen under 20 years of age. Individuals with familial dysbetalipoproteinemia have multiple clinical presentations. The symptoms of familial dysbetalipoproteinemia include the following

• Xanthomas - A deposit of fatty material in the skin, known as xanthomas, may appear on the palms of the hands, eyelids, soles of the feet, or on ankles, knees, and elbows. Around 50 percent of individuals develop cutaneous xanthomas. These xanthomas are usually eruptive or palmar crease xanthomas. Other variants like tendon xanthomas, tuberous xanthomas, and xanthelasma are common in other mixed familial dyslipidemia disorders. Still, not specifically familial dysbetalipoproteinemia. The palmar crease xanthomas resolve with time with treatment.

• Atherosclerosis - Some individuals may initially present with signs of premature atherosclerosis (angina or acute coronary syndrome). The presence of chest pain (angina) or other signs of coronary artery disease may occur at a young age.

• Pancreatitis with hypertriglyceridemia.

• Cramping of one or both calves while walking.

• Non-healing sores on the toes.

• Stroke-like symptoms such as drooping of one side of the face, trouble speaking, weakness of an arm or leg, and disbalance.

• The most common types of cardiovascular disease in individuals with familial dysbetalipoproteinemia are coronary artery disease (CAD) and peripheral artery disease (PAD).

• Insulin resistance.

• Obesity.

What Is the Epidemiology of Familial Dysbetalipoproteinemia?

The APOE gene gives instructions for making a protein known as apolipoprotein E. This particular protein combines with the lipids (fats) in the body and forms molecules called lipoproteins. Lipoproteins are the molecules that are responsible for carrying cholesterol and other fats through the bloodstream. Maintaining a normal cholesterol level is important for preventing disorders affecting the heart and blood vessels (cardiovascular diseases), such as heart attack and stroke.

There are three different types (alleles) of the APOE gene. The important alleles are called E2, E3, and E4. E3 is the most common allele found in most individuals.

The prevalence of dysbetalipoproteinemia varies depending on the condition. Both men and postmenopausal women are more prone to the condition than premenopausal women due to the lack of estrogen. Estrogen hormone affects lipolytic processing and expression of LDL (low deficiency lipoprotein). Dysfunctional lipolytic processing with increased VLDL (very low deficiency lipoprotein) production causes hypertriglyceridemia. In addition, impaired receptor clearance leads to hypercholesterolemia.

How Is Familial Dysbetalipoproteinemia Diagnosed?

Familial dysbetalipoproteinemia can be detected by the following examinations:

• Genetic Testing for Apolipoprotein E (APOE) - This test accesses the individual's DNA to determine the type of combination of the APOE gene present.

• Lipid Panel Blood Test - This complete cholesterol test determines the total amount of triglycerides and cholesterol in the blood.

• Triglyceride Level - This is a blood test that measures the number of triglycerides in the blood.

• Very Low-density Lipoprotein Test - This is a blood test that is used to measure the amount of very low-density lipoprotein in the blood.

How Is Familial Dysbetalipoproteinemia Treated?

The treatment of familial dysbetalipoproteinemia is a combination of therapy with lifestyle modifications and medical treatment. Lifestyle modifications are important to reduce the intake of fat and carbohydrate. Individuals with familial dysbetalipoproteinemia respond well to diet modifications. Diet modifications include reducing the intake of saturated fats with unsaturated fat and long-chain polyunsaturated fatty acids.

Insulin resistance is common among people with familial dysbetalipoproteinemia, and it leads to lower plasma lipid levels. So, a low carbohydrate diet is also recommended for such people. Obesity is also a risk factor in individuals whose weight reduction can lead to lower triglyceride levels. Evaluation and elimination of secondary risk factors such as type 2 diabetes, hypothyroidism, and metabolic syndrome have been found to improve triglyceride levels.

When diet modifications are not enough to maintain lipid levels, drugs such as statins with fibrates can be used and have been found to improve the levels of low-density lipoproteins. Non-HDL cholesterol should be carefully monitored as compared to LDL cholesterol which is usually low. Monotherapy with statin makes the individuals hypercholesterolemic, and the fibrates improve the lipid profiles.

How Is the Prognosis of Familial Dysbetalipoproteinemia?

Individuals with familial dysbetalipoproteinemia have a good prognosis. Usually, they respond well to lifestyle modifications and medical treatment. Patients with a higher level of triglyceride and total cholesterol have an increased risk for complications than those without elevated levels. Early diagnosis and treatment result in the best prognosis for patient longevity.

What Are the Complications of Familial Dysbetalipoproteinemia?

Complications of familial Dysbetalipoproteinemia include the following:

• Coronary Artery Disease - This is the narrowing or blockage of the major blood vessels of the heart.

• Peripheral Vascular Disease - This is a condition in which the narrowed blood vessels reduce the blood flow to the arms and legs.

• Obesity.

• Insulin resistance.

• Acute pancreatitis with elevated triglyceride levels.

• Atherosclerosis - This is the build-up of fatty substances and cholesterol in and around the blood vessels.

Conclusion

Familial dysbetalipoproteinemia, also known as formerly type III hyperlipoproteinemia, is a rare disorder of lipoprotein metabolism. It is characterized by moderate to severe hypercholesterolemia and hypertriglyceridemia caused by the accumulation of cholesterol-rich particles in the blood. Prompt detection with genetic testing will help guide the treatment. The primary goal of treatment for familial dysbetalipoproteinemia is to reduce non-HDL (high-density lipoprotein) cholesterol. Prognosis can be improved with dietary therapy or combination treatment with statin and fibrate combination, and patient outcomes can be improved.