Continuing Education Activity

Dysbetalipoproteinemia, also known as familial dysbetalipoproteinemia, hyperlipoproteinemia type III (HLP3), or broad β disease, is a genetic abnormality in apolipoprotein E2 (apoE) that causes impaired lipoprotein metabolism. This lipoprotein metabolic abnormality promotes fatty deposit accumulation on arterial walls, elevated serum triglycerides and total cholesterol, and the development of palmar xanthomas. Dysbetalipoproteinemia is associated with complications, including coronary artery disease and peripheral vascular disease. Establishing the presence of the dysbetalipoproteinemia phenotype and the APOE genotype, which are the underlying etiologies of dysbetalipoproteinemia, is essential for diagnosis. The management of dysbetalipoproteinemia primarily consists of dietary lipid restriction and pharmacologic therapy with statins and fibrates. Clinicians should monitor patients during treatment using non-high-density lipoprotein cholesterol (non-HDL-C) testing to ensure that atherogenic lipoproteins are well controlled. This activity for healthcare professionals aims to enhance learners' competence in selecting appropriate diagnostic tests, managing dysbetalipoproteinemia, and fostering effective interprofessional teamwork to improve outcomes.

Objectives:

• Identify the etiology of familial dysbetalipoproteinemia disease.

• Implement the recommended evaluation of familial dysbetalipoproteinemia.

• Determine the proper treatment strategy for patients with dysbetalipoproteinemia.

• Collaborate with interprofessional healthcare team members to improve outcomes for patients with dysbetalipoproteinemia.

Introduction

Dysbetalipoproteinemia, also known as familial dysbetalipoproteinemia (FD), hyperlipoproteinemia type III (HLP3), or broad β disease, is a genetic lipid disorder characterized by increased accumulation of triglyceride-rich remnant lipoproteins. The accumulation of lipoproteins is due to impaired remnant clearance. Most patients with dysbetalipoproteinemia are homozygous for the apolipoprotein E2 (APOE) gene. Additionally, FD is associated with poor adherence of apolipoprotein E to the LDL receptors. Although FD is an autosomal recessive condition in most cases, 10% of cases are due to autosomal dominant mutations. This lipoprotein metabolic abnormality promotes fatty deposit accumulation on arterial walls, elevated serum triglycerides and total cholesterol, and the development of palmar xanthomas.[1] Dysbetalipoproteinemia is associated with complications, including coronary artery disease and peripheral vascular disease. FD has a 10-fold increased risk for premature coronary artery disease compared to population-based controls.[2] 

Establishing the presence of the dysbetalipoproteinemia phenotype and the APOE genotype, which are the underlying etiologies of dysbetalipoproteinemia, is essential for diagnosis. The management of dysbetalipoproteinemia primarily consists of dietary lipid restriction and pharmacologic therapy with statins and fibrates. Clinicians should monitor patients during treatment using non–high-density lipoprotein cholesterol (non–HDL-C) testing to ensure that atherogenic lipoproteins are well controlled.[1]

Etiology

Familial dysbetalipoproteinemia (FD) is caused by a genetic mutation in the apolipoprotein E (APOE) gene, leading to Apo E2/E2 homozygotes. The most common isoform of APOE is APOE3. The primary cause of dysbetalipoproteinemia is the presence of another isoform of APOE called APOE2, which differs from APOE3 by a single amino acid substitution of cysteine for arginine at position 158.[3]

Dysbetalipoproteinemia primarily results in the accumulation of remnant lipoprotein. ApoE is found on triglyceride-rich lipoprotein particles like chylomicrons, very low-density lipoproteins (VLDL), and intermediate-density lipoproteins (IDL). It mediates their catabolism by binding to receptors in the liver. The presence of APOE2 isoform on these triglyceride-rich particles leads to impaired binding of lipoprotein particles to lipoprotein receptors, such as LDL receptors (LDLR), LDLR-related proteins (LRP), and heparan sulfate proteoglycans (HSPG).

HSPG contains a single transmembrane polypeptide strand (core protein) called heparan sulfates, to which sugar polymers are attached.[4] They capture the lipoproteins and other ligands. Out of many HSPG species, syndecan 1 HSPG-R is involved in remnant clearance, found in the space of Disse, where the remnant particle clearance occurs. This impaired binding results in the defective removal of chylomicrons and VLDL remnants, leading to their accumulation in circulation, which eventually causes premature atherosclerosis.

Epidemiology

The APOE gene locus has 3 main variants, namely E2, E3, and E4, which results in 3 homozygous (E2E2, E3E3, and E4E4) and 3 heterozygous (E2E3, E3E4, and E4E2) genotypes. The E3E3 is the most frequent APOE genotype in humans; hence, the E3E3 form is considered the wild type.[5] Either homozygous apo E2/E2 genotype, which is more common, or heterozygosity apo E3-Leiden and apoE2 (Lys1463Gln), which are rare, must be present to have a phenotypical presentation or elevated triglyceride (TG), and total cholesterol.[6][7][8] Autosomal recessive mutations are more common. Autosomal dominant mutations cause 10% of familial dysbetalipoproteinemia cases.[9]

The prevalence of dysbetalipoproteinemia varies depending on the definition used to determine the condition. Previous studies differed in their inclusion or exclusion of E2/E2 genotype, autosomal dominant mutations, VLDL-cholesterol/plasma TG ratio >0.30 on gel electrophoresis, TG/ApoB ratio, and total cholesterol/Apo B ratio. One study definition states if a patient has a total cholesterol level of more than the 90th percentile and an E2/E2 genotype, they are diagnosed with dysbetalipoproteinemia. The prevalence demonstrated in this study was 0.1% or 1 in 1000 of the general population.[10][11]

In contrast, another earlier stated a VLDL-cholesterol/plasma TG ratio >0.30 on gel electrophoresis was needed to diagnose the disease. This study had a prevalence of 0.4% in men and 0.2% in women.[12] Another study found a similar prevalence among CAD patients at 0.7% in controls and 2.7% in those with CAD. However, the first study did not include autosomal dominant mutations, excluding a portion of type III dysbetalipoproteinemia. If these patients had been included, the prevalence of FD would be 0.12% or 1 in 825. The second study did not include the E2/E2 genotype or autosomal dominant patients. Another study that used the measurement of apoB/TC with a cut-off threshold of <0.15 as the diagnostic indicator determined the prevalence of FD was 2.7%. However, another study using a similar indicator, though TG was included, reported a prevalence of 1.7%.[13][14][13] These studies included patients with E2/E2 but not those with autosomal dominant mutations.

In the homozygous APOE2 genotype, there are more hypolipidemic rather than hyperlipidemic.[15] Accumulation of remnant occurs when there is an accompanying secondary genetic or acquired defect, including decreased remnant clearance, decreased LDL receptor activity, and increased VLDL production.[3] The interaction of environmental and genetic factors is required for phenotypic expression.[16][17]

Men and postmenopausal women are more predisposed to the condition than premenopausal women as they do not have the benefit of estrogen. Estrogen affects the lipolytic process and LDL receptor expression.[3] Dysfunctional lipolytic processing of remnants with increased VLDL production causes hypertriglyceridemia, and impaired receptor clearance leads to hypercholesteremia.

History and Physical

Patients with dysbetalipoproteinemia may have a variety of clinical presentations. Approximately 50% of patients develop cutaneous xanthomas, most commonly the eruptive or palmar crease type of xanthomas.[18] Tuberous xanthomas, tendon xanthomas, and xanthelasma are common in most mixed familial dyslipidemia disorders but not specific to familial dysbetalipoproteinemia.[19] Palmar xanthomas and tuberous xanthomas are more commonly seen when levels are more than 1000. Once treatment is initiated, palmar crease xanthomas resolve with time. Some patients may first present with signs of premature atherosclerosis (eg, angina or acute coronary syndrome) or pancreatitis with hypertriglyceridemia.[20]

The most common types of cardiovascular disease in patients with familial dysbetalipoproteinemia are peripheral artery disease (PAD) and coronary artery disease (CAD). A cross-sectional study of 305 European subjects demonstrated a 19% prevalence of CAD, 11% prevalence of PAD, and 4% of cerebrovascular disease in FD patients.[21] Insulin resistance and obesity are also common presentations.[22]

Patients with coronary artery disease secondary to dysbetalipoproteinemia generally present in the same manner as any other patient with CAD. A common symptom is chest pain with exertion or at rest. Less frequent symptoms include fatigue, exertional shortness of breath, peripheral edema, and transient nonspecific chest discomfort.[23] Patients may have peripheral artery disease without symptoms or with associated symptoms, including intermittent claudication, acute limb ischemia, or chronic limb ischemia.[24]

Evaluation

Establishing the presence of the dysbetalipoproteinemia phenotype and the APOE genotype, which are the underlying etiologies of dysbetalipoproteinemia, is essential for diagnosis.[1] Positive clinical findings (eg, palmar xanthomas and tuberous xanthomas) and an initial fasting lipid profile demonstrating increased total cholesterol and triglyceride levels raise clinical suspicion of FD. Levels of total cholesterol and triglyceride (TG) levels are usually within the range of 300 to 1000 mg/dL with an approximately similar range or disproportionally high triglyceride or low low-density lipoprotein cholesterol (LDL-C) levels as opposed to total cholesterol (TC).[25] Genotyping with an evaluation of APOE with the E2/E2 genotype is usually needed for diagnosis, and in cases of autosomal dominant inheritance, full APOE sequencing may be required.[26][27]However, with lipid studies alone, FD can not be differentiated from other APOE genotype variant abnormalities that cause dyslipidemia (eg, familial hypercholesterolemia, hypertriglyceridemia, or lipoprotein glomerulopathy). Therefore, the dysbetalipoproteinemia phenotype must be determined as well. The standard studies utilized are ultracentrifugation and polyacrylamide gradient gel electrophoresis (PGGE).[28] In areas where these diagnostic studies are unavailable, apoB testing can be utilized to assess for the dysbetalipoproteinemia phenotype. The following methods and thresholds, which all have a relatively high sensitivity and specificity, may be used to diagnose dysbetalipoproteinemia.[1][29]

• Ultracentrifugation: 
  • VLDL-cholesterol/VLDL-triglyceride (TG) molar ratio: >0.97
  • VLDL-cholesterol/total plasma TG molar ratio: >0.69
• Apolipoprotein B (ApoB)/TC ratio: <0.15 g/mmol
• Non-HDL-C/apoB ratio: >4.91 mmol/g
• ApoB <1.2 g/l, triglyceride at least 1.5 mmol/l, triglyceride/apoB <10 mmol/g, and TC/apoB at least 6.2 mmol/g
• Polyacrylamide gradient gel electrophoresis (PGGE)
  • Quantitative stains for small VLDL and intermediate-density lipoprotein (IDL) with little or no LDL
  • Qualitative: Area under the curve IDL-range/LDL-range ratio >0.5

β quantification is also a valuable biochemical test for dysbetalipoproteinemia as it detects “β-VLDL” in the supernatant after ultracentrifugation and determines if the VLDL to triglyceride ratio is high.[22] Both features are hallmarks of the disease. However, these specialized tests are not widely available and cannot be practically done in all patients with mixed hyperlipidemia. Using apoB as a ratio to total or non-HDL cholesterol or in a multi-step algorithm initially to determine if additional evaluation is indicated is also a promising approach. More comprehensive implementation of diagnostic pathways using apo B could lead to the more rational use of specialized investigations and consistent detection of patients with dysbetalipoproteinemia. Therefore, many cases are likely to remain undiagnosed if a consistent, evidence-based approach to diagnosing dysbetalipoproteinemia is not utilized.

Treatment / Management

The management of dysbetalipoproteinemia is a multistep approach combining lifestyle modifications and medical treatment. Dietary modifications are the primary component of lifestyle changes that have the most significant impact on patients with dysbetalipoproteinemia.[30]

Lifestyle Modifications

The diet recommended for patients with FD generally consists of minimally processed, high-fiber, plant-based foods (eg, vegetables,  whole grains, legumes, and nuts) and has been found to improve hyperlipidemia in most patients.[95] Dietary changes should reduce saturated fat intake and instead consume unsaturated fats and long-chain polyunsaturated fatty acids.[30][31][32] Specific dietary modifications include increasing intake of lean proteins, vinegar, fish oil, tea, and cinnamon and reducing alcohol consumption and daily total calories. Patients should also be instructed to lose weight and increase their daily exercise, as weight reduction in these patients has led to lower triglyceride levels.[95]

A low carbohydrate diet is also recommended, as concomitant insulin resistance is common among individuals with dysbetalipoproteinemia. Additionally, a diet low in carbohydrates has been associated with lower plasma lipid levels.[33] Evaluation and optimization of secondary risk factors, including hypothyroidism, type 2 diabetes mellitus, and metabolic syndrome, demonstrated improvement of triglyceride levels.[34]

Pharmacological Therapy

When dietary modifications are insufficient in optimizing lipid levels, statins with fibrates are the mainstay of therapy and demonstrate improvement in LDL levels. Clinicians should focus on non-HDL cholesterol as LDL-C is usually low.[34] Statin monotherapy leaves patients hypercholesterolemic, and adding fibrates improves lipid profiles.[35]

There are limited randomized controlled trials specific for familial dysbetalipoproteinemia patients evaluating the effect of lipid-lowering medications. The completed trials did have indeterminate endpoints in terms of on-target lipid levels. Overall trials did demonstrate a reduction in LDL and total cholesterol levels.[36][37][38][39] The role of PCSK9 inhibitors remains unclear in FD. Some studies report that the dominant portion of apoB-containing lipoproteins is decreased with PCSK9 inhibition, such as LDL in mixed hyperlipidemia and hypercholesterolemia, and cholesterol-rich VLDL, remnants, and LDL in familial dysbetalipoproteinemia. PCSK9 inhibitors could be helpful in patients who are resistant or intolerant to statin or fibrate therapy.[40]

Differential Diagnosis

Differential diagnosis of dysbetalipoproteinemia remains broad as dyslipidemia and xanthomas can be present in other conditions, including:

• Combined hyperlipidemia: ApoB levels are elevated with increases in both LDL and VLDL secondary to overproduction.[41] Unlike dysbetalipoproteinemia, which does not have an increase in LDL-C.
• Nephrotic syndrome: Increases the production of all cholesterol variants.[42]
• Hepatic lipase deficiency: Deficiency in hepatic lipase activity is required for converting IDL to LDL. HDL is usually elevated as hepatic lipase manages the metabolism of HDL.[43] Phenotypically presents similar to dysbetalipoproteinemia.
• Polygenic hypercholesterolemia
• Metabolic syndrome
• LPL deficiency
• Hypothyroidism
• Familial hypertriglyceridemia

Familial dysbetalipoproteinemia can also be mistaken for familial hypercholesterolemia. Familial hypercholesterolemia is a genetic lipid disorder with defective LDL receptors, leading to increased LDL in the peripheral circulation. Usually, LDL cholesterol is low in these patients. However, they can sometimes be falsely elevated when the Friedwalds formula calculates LDL-C. The Friedewald formula subtracts the cholesterol content in HDL and VLDL from the total cholesterol to estimate the fasting plasma concentration of LDL-C. Cholesterol in VLDL is estimated by dividing the total TG concentration by 5. However, in familial hypercholesterolemia, the cholesterol content in VLDL particles and remnants is increased, with the result that the Friedewald formula underestimates cholesterol in VLDL and overestimates cholesterol in LDL.[44] Evaluation of causes of xanthomas and xanthelasmas is also essential.

Toxicity and Adverse Effect Management

The combination of fibrate and statin therapy is associated with an increased risk of myopathies. In dysbetalipoproteinemia, the benefits of combined statin-fibrate therapy would outweigh the risks associated with these medications. Patient education on the potential side effects of combination therapy is essential.[45]

Prognosis

When managed, patients with familial dysbetalipoproteinemia have a good prognosis. Commonly, patients 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. Remnant cholesterol is the abundant cholesterol in dysbetalipoproteinemia. Increased remnant cholesterol is causally associated with an increased risk of ischemic heart disease and is also associated with a higher risk of all-cause mortality.[46][47]

Complications

Complications of dysbetalipoproteinemia include the following:[48]

• Peripheral vascular disease
• Coronary artery disease
• Insulin resistance
• Acute pancreatitis [49]

In addition, a predisposition to atherosclerosis is noted. Early diagnosis and treatment will help manage complications.

Deterrence and Patient Education

Lifestyle modifications are essential with a good dietician to guide therapy. Prompt medical assessment is also necessary to improve patient outcomes through early recognition of symptoms with the management of complications. Patients do not understand that triglycerides are analyzed along with cholesterol. The possibility of complications should be made known to the patient of dysbetalipoproteinemia, emphasizing the increased risk of cardiovascular disease. Clinicians should advise patients that their condition responds well to simple dietary modifications, exercise, and weight loss interventions.[48] A trained dietitian provides thorough diet instructions. Exercise counseling may be helpful in treating dyslipidemia and reducing the risk of symptomatic cardiovascular disease. In addition, the clinician should stress the importance of alcohol intake of no more than 1 drink per day, provide instructions on the use of medications, and provide comprehensive diabetes education to diabetic patients.

Enhancing Healthcare Team Outcomes

Dysbetalipoproteinemia should be considered in all cases of abnormal lipid profiles. Phenotypic presentation is not always present. A high degree of suspicion is needed. Prompt evaluation with genetic testing will help guide therapy. The goal of treatment for familial dysbetalipoproteinemia patients is reducing non–HDL-C. The prognosis can be improved with dietary therapy and treatment with a statin and fibrate combination. An interprofessional management approach includes primary care clinicians, specialists, mid-level practitioners (PA/NP), nursing staff, and pharmacists collaborating to improve patient outcomes.