Continuing Education Activity

Familial dysbetalipoproteinemia is a condition in which there abnormality in apoE, which leads to elevated triglycerides and total cholesterol with palmar xanthomas. This disease is associated with complications, including coronary artery disease and peripheral vascular disease. This activity reviews the evaluation and treatment of familial dysbetalipoproteinemia and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Summarize the etiology of familial dysbetalipoproteinemia disease.
• Review the evaluation of familial dysbetalipoproteinemia.
• Describe the management of familial dysbetalipoproteinemia.
• Outline some interprofessional strategies to improve outcomes for patients with familial dysbetalipoproteinemia.

Introduction

Familial dysbetalipoproteinemia (FD), or type III hyperlipoproteinemia (Fredrickson-Levy-Lees Classification) is a genetic lipid disorder characterized by increased accumulation of triglyceride-rich remnant lipoproteins. It is associated with an increased risk for premature atherosclerotic cardiovascular disease. FD had a 10-fold increased risk for premature coronary artery disease compared to population-based controls.[1]

Etiology

Familial Dysbetalipoproteinemia is caused by a genetic mutation in the gene for apolipoprotein E (ApoE) 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 is different from the ApoE3 by a single amino acid substitution of cysteine for arginine at position 158.[2]

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) and 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 [LDL receptors(LDLR), LDLR-related proteins (LRP), and heparan sulfate proteoglycans (HSPG)]. HSPG contains a single transmembrane, polypeptide strand (core protein) to which sugar polymers are attached called heparan sulfates.[3] They capture the lipoproteins and other ligands. Out of many HSPG species, syndecan 1 HSPG-R is involved in remnant clearance, which is found in the space of Disse, where the remnant particles clearance occurs. This impaired binding results in defective removal of chylomicrons and VLDL remnants leading to their accumulation in the circulation. This eventually causes premature atherosclerosis.

Epidemiology

The APOE gene locus has three main variants, namely E2, E3, and E4, which results in three homozygous (E2E2, E3E3, and E4E4) and three heterozygous (E2E3, E3E4, and E4E2) genotypes. The E3E3 is the most frequent APOE genotype in humans and hence E3E3 form is considered the wildtype.[4] Either homozygous (more common) apo E2/E2 genotype or heterozygosity (rare) apo E3 Leiden and apoE2 (Lys1463Gln) must be present to have a phenotypical presentation or elevated triglyceride (TG) and total cholesterol.[5][6][7]. Autosomal recessive mutations are more common and 10% of FD cases are caused by autosomal dominant mutations.

Dysbetalipoproteinemia prevalence is variable 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 > 90th percentile & E2/E2 genotype, they are diagnosed with dysbetalipoproteinemia. Prevalence demonstrated in this study was 0.1% or 1 in 1000 in the whole population.[8][9] 

In contrast, another older study definition 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.[10] In another study, similar diagnostic values among CAD patients found 0.7% in controls and 2.7% in those with CAD. This first study did not include autosomal dominant mutations, excluding a portion of type III dysbetalipoproteinemia. If included would be 0.12% or 1 in 825. The second study did not include E2/E2 genotype, let alone autosomal dominant. A different definition was used in another study that used the measurement of apoB/TC (<0.15) as an indicator. This study found the prevalence to be 2.7% using Blom et al.[11] The last study used a similar definition but did include TG as well, which did demonstrate a prevalence of 1.7% with the Sniderman et al.[12] Both studies included E2/E2 but did not include autosomal dominant mutation.

In homozygous apoE2 genotype, there are more hypolipidemic rather than hyperlipidemic.[13] Accumulation of remnant occurs when there is a concomitant secondary genetic or acquired defect, including decreased remnant clearance, decreased LDL receptor activity, and increased VLDL production.[2] Interaction of environmental and genetic factors is required for phenotypic expression.[14][15] 

Men and postmenopausal women are more predisposed than premenopausal women as they do not have the benefit of estrogen. Estrogen affects lipolytic processing and LDL receptor expression.[2] Dysfuntiontional lipolytic processing of remnants with increased VLDL production causes hypertriglyceridemia. Impaired receptor clearance leads to hypercholesteremia.

History and Physical

Familial Dysbetalipoproteinemia patients have a variety of clinical presentations. Approximately 50% of patients develop cutaneous xanthomas.  which are usually eruptive xanthomas or palmar crease xanthomas.[16] Tuberous xanthomas, tendon xanthomas, & xanthelasma are common in most mixed familial dyslipidemia disorders but not specific to familial dysbetalipoproteinemia.[17] Once treatment is initiated, palmar crease xanthomas resolve with time. Some patients may first present with signs of premature atherosclerosis (angina or acute coronary syndrome) or pancreatitis with hypertriglyceridemia.

The most common types of CVD in patients with FD are peripheral artery disease (PAD) and coronary artery disease (CAD). A cross-sectional study of 305 European subjects demonstrated 19% prevalence of CAD, 11% prevalence of PAD and 4% prevalence of cerebrovascular disease in FD patients.[18] Insulin resistance and obesity are also common presentations.[19] 

Evaluation

Initial evaluation with a fasting lipid profile should be completed. Increased total cholesterol and increased triglyceride levels should raise suspicion. Levels of total cholesterol and TG levels are usually within the range of 300-1000 mg/dL with an approximate similar range or disproportionally high triglyceride or low LDL-C levels compared with TC.[20] The presence of palmar xanthomas and tuberous xanthomas should raise suspicion, as they are more commonly seen in levels >1000. Measurement of VLDL and non-LDL are essential as well.

Three methods to diagnosis familial dysbetalipoproteinemia either by apoB/TC ratio < 0.15 g/mmol, or apoB less than 1.2 g/l, triglyceride at least 1.5 mmol/l, triglyceride/apoB less than 10 and TC/apoB at least 6.2, or use of polyacrylamide gradient gel electrophoresis, which shows small VLDL and IDL. An IDL-range AUC/LDL-range AUC ratio of > 0.5 all these methods yield relatively high sensitivity and specificity.[21]

Genotyping with an evaluation of ApoE with E2/E2 genotype. If negative autosomal dominant variant may be present. May require full APOE sequencing to diagnose autosomal dominant.[22][23]

Treatment / Management

Treatment of familial dysbetalipoproteinemia is a multistep approach with combination therapy with both lifestyle modifications and medical treatment. Lifestyle modifications are essential with reduced intake of fat and/or carbohydrate.[24] Patients with familial dysbetalipoproteinemia respond exceptionally well to dietary therapy. Dietary therapy includes reducing saturated fat intake with replacement, including unsaturated fat and long-chain polyunsaturated fatty acids.[25] 

A low carbohydrate diet is also recommended as concomitant insulin resistance is common among individuals with familial dysbetalipoproteinemia and is associated with lower plasma lipid levels.[26] Obesity is a modifiable risk factor in patients in whom reduction in weight can lead to lower triglyceride levels. Evaluation and optimization of secondary risk factors including hypothyroidism, type 2 diabetes mellitus, metabolic syndrome demonstrated improvement of triglyceride levels.[27]

When dietary modifications are insufficient in optimizing lipid levels, statins with fibrates are the mainstay of therapy and demonstrated improvement in LDL levels. It is important to focus on non-HDL cholesterol as LDL-C is usually low.[27] Statin monotherapy leaves patients hypercholesterolemic, and the addition of fibrates improves lipid profiles.[28] 

There is a limited number of randomized controlled trials specific for familial dysbetalipoproteinemia patients evaluating the effect of lipid-lowering drugs. The trials that were completed did have indeterminate endpoints in terms of on-target lipid levels. Overall trials did demonstrate a reduction in LDL and total cholesterol levels.[29][30][31][32] The role of PCSK9 inhibitors remains unclear in familial dysbetalipoproteinemia.

Differential Diagnosis

Differential diagnosis remains broad as dyslipidemia and xanthomas can be present in other forms of:

• Combined hyperlipidemia - elevated levels of ApoB with increases in both LDL and VLDL secondary to overproduction.[33] Unlike dysbetalipoproteinemia, which does not have an increase in LDL-C
• Nephrotic Syndrome-will causes an increase in the production of all cholesterol variants.[34]
• Hepatic Lipase Deficiency- deficiency in hepatic lipase activity which is required for conversion of IDL to LDL. HDL is usually elevated as hepatic lipase manages the metabolism of HDL.[35] Phenotypically present similarly to dysbetalipoproteinemia
• Polygenic hypercholesterolemia
• Metabolic syndrome
• LPL deficiency
• Hypothyroidism
• Familial hypertriglyceridemia

Evaluation of causes of xanthomas and xanthelasmas is essential.

FD can also be mistaken for familial hypercholesterolemia. Familial hypercholesterolemia is a genetic lipid disorder where the LDL receptors are defective that leads to increased LDL in the peripheral circulation. Usually, in patients with FD, LDL cholesterol is low. However, sometimes they can be falsely elevated when the Friedwalds formula is used to calculate 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 FD, 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.[36]

Toxicity and Adverse Effect Management

The combination of fibrate and statin therapy is associated with an increased risk of myopathies. In Dysbetalipoproteinemia benefits of combined statin-fibrate therapy would outweigh the risks associated with these medications. Patient education of potential side-effects of combination therapy is essential.[37]

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.

Complications

Complications include peripheral vascular disease, obesity, coronary artery disease, insulin resistance.[38] There is always a risk of acute pancreatitis with elevated TG levels. 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. Medical compliance is also necessary to improve patient outcomes—early recognition of symptoms with the management of complications.

Enhancing Healthcare Team Outcomes

Familial 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 goals of therapy for familial dysbetalipoproteinemia patients are reducing non-HDL-C. Prognosis can be improved with dietary therapy and/or treatment with statin and fibrate combination. An interprofessional management approach includes the family clinicians, specialists, mid-level practitioners (PA/NP), nursing staff, and pharmacists, all collaborating to achieve improved patient outcomes.