Introduction

Familial combined hyperlipidemia (FCH) is a common and prevalent hereditary lipid disorder. The inherited primary dyslipidemia is named after its variable expression of increased plasma cholesterol and triglyceride levels, which affects at least two family members.[1] In 1973, FCH was initially described as an autosomal dominant inherited lipid disorder by Goldstein et al, Rose et al, and Nikkila et al. However, it was later found to have a multigenic mode and complex inheritance.[2][3]

FCH manifests as increased serum cholesterol levels (hypercholesterolemia) and/or increased triglycerides (hypertriglyceridemia).[4] It may also present as isolated increases in apolipoprotein B (apoB) with a serum lipid profile in the reference range.[4] The estimated prevalence of FCH is approximately 0.5 to 4%.[5] The genetic element of FCH has not been fully understood to date.[6] Associated metabolic dysfunction includes increased very low-density lipoprotein (VLDL) and slowed removal of low-density (LDL) and triglyceride-rich lipoproteins.[6] 

The abnormal increases in plasma lipids and triglycerides are significant risk factors for cardiovascular disease (CVD) and CVD-related mortality. The risk for mortality increases in individuals with underlying metabolic comorbidities such as type 2 diabetes (T2DM), obesity, alcohol dependence, hypothyroidism, and liver disease.[4] FCH is most commonly seen as an underlying risk factor in individuals with coronary heart disease and patients with acute myocardial infarction.[7]

The management of FCH patients includes therapeutic agents to lower cholesterol and triglyceride levels to prevent cardiovascular disease. FDA-approved treatments include HMG-CoA reductase inhibitors (statins), fibric acid derivatives (fibrates), bile acid sequestrants, PCSK9 inhibitors, niacin, and ezetimibe.[8][9] Other treatment options include omega-3 fatty acids (fish oil) and MTTP inhibitors (lomitapide).

Etiology

As previously stated, the genetic element of FCH has not been fully understood to date.[6] The pattern of inheritance of FCH was initially reported to be autosomal dominant in 1973 by Goldstein et al.[2] Later research specified and proposed that FCH be familial or nonfamilial, making it a multigenic mode and complex inheritance.[2][3] 

Alongside the hereditary aspect of FCH, other risk factors contributing to the pathogenesis include environmental elements.[3] The pathophysiologic mechanisms of FCH result in metabolic dysfunction, causing increased very low-density lipoprotein (VLDL), slowed removal of low-density (LDL) and triglyceride-rich lipoproteins, and unregulated overproduction of apo-B lipoproteins in the liver.[6][3]

Epidemiology

The estimated prevalence of FCH is approximately 0.5% to 4%.[5] Roughly 10% to 20% of individuals who have experienced premature myocardial infarction are found to have familial combined hyperlipidemia.[10] According to a study conducted by Paramsothy et al in 2009, the prevalence of combined hyperlipidemia demonstrates variation among different racial groups. The study found that Hispanics exhibited higher rates of combined hyperlipidemia compared to whites. Conversely, African-Americans had lower rates of combined hyperlipidemia than whites, despite having higher body mass index levels and abdominal adiposity. This suggests that African-Americans have lower odds of developing combined hyperlipidemia when compared to individuals of white ethnicity.[11]

Pathophysiology

Familial combined hyperlipidemia is believed to be caused by an underlying pathophysiological mechanism characterized by hepatic overproduction of lipoprotein particles containing apoB-100, namely VLDL and LDL. This results in elevated levels of plasma total cholesterol, triglycerides, and apoB. Furthermore, individuals with FCH exhibit reduced HDL cholesterol levels and an increase in small dense LDL (sdLDL) and remnant lipoprotein particles.[12] 

Initially, it was believed that FCH was inherited through a dominant monogenic manner. However, subsequent studies proposed a more complex polygenic inheritance to explain the variability in the lipid phenotype. Several loci, specifically at 9p, 16q, and 11q, have been linked to LDL size in FCH patients.[13] Notably, the gene encoding Upstream Transcription Factor 1 (USF1) has been associated with FCH. USF1 regulates various genes related to glucose and lipid metabolism.[14][15]

Patients with FCH are noted to have delayed clearance of chylomicron and VLDL remnants.[16] One of the genes involved in their clearance pathways is the LPL gene.[17] A recent study has linked a mutation that substitutes aspartic acid with asparagine at position 151 in the LPL gene to an increased incidence of FCH.[18]

Impairment in the low-density lipoprotein receptor (LDLR) can increase LDL levels. Mutations in the LDLR may lead to FCH.[19] Proprotein convertase subtilisin kexin type 9 (PCSK9) is associated with the cholesterol synthesis markers lathosterol and desmosterol. PSCK9 levels are also a stimulus for LDLR degradation. A study by Brouwers et al demonstrated that PCSK9 levels are heritable and increased in patients with FCH.[20]

History and Physical

Patients with familial combined hyperlipidemia often have a family history of dyslipidemia, premature cardiovascular disease, and premature death from heart disease or stroke. Aside from the positive familial history, FCH patients may exhibit symptoms such as chest discomfort, difficulty breathing, or leg pain while walking. Additionally, they may possess risk factors for cardiovascular conditions, such as hypertension, diabetes, and obesity.[21]

FCH is a complex disorder with variable expression and penetrance, and the age of onset and severity of symptoms can differ among affected individuals within the same family. Therefore, obtaining a detailed family history of hyperlipidemia, cardiovascular disease, and premature death is crucial, especially among first-degree relatives. 

The physical examination of a patient with FCH is typically unremarkable, with no specific physical findings associated with the disorder. However, patients with FCH may have signs of cardiovascular disease such as hypertension, peripheral arterial disease (PAD), or carotid bruits. Though they are rare in patients with FCH, a careful examination of the skin may reveal the presence of xanthomas. These cholesterol deposits are often associated with high cholesterol levels or triglycerides in the blood. They may indicate an underlying metabolic disorder such as familial combined hyperlipidemia or familial hypercholesterolemia.[22][23]

Furthermore, a comprehensive cardiac assessment may detect the existence of a murmur, indicating potential valvular heart disease, or indications of heart failure, such as peripheral edema, jugular venous distension, and hepatomegaly. A neurological examination may reveal the presence of focal deficits, suggesting cerebrovascular disease.

Evaluation

Familial combined hyperlipidemia can present with varying laboratory findings in different individuals and members of the same family. The laboratory results may reveal elevated levels of serum triglycerides, total cholesterol, mixed triglycerides, increased very-low-density lipoproteins (VLDLs), increased low-density lipoproteins (LDLs), raised levels of apolipoprotein B (apo-B), or reduced levels of high-density lipoprotein (HDL).[7] Elevations in triglycerides and apo-B may exhibit values of 1.5 mmol/L and 1.2 g/L, respectively.[1] 

Several studies have reported an association between FCH and increased carotid intima-media thickness (IMT), a marker of subclinical atherosclerosis. Therefore, a carotid ultrasound may be performed to assess the presence of subclinical atherosclerosis in patients with FCH.[24][25]

Treatment / Management

Familial combined hyperlipidemia, the most commonly reported genetic dyslipidemia, increases the risk of early atherosclerosis expression.[1] The management of FCH surrounds reducing the increased lipid levels in circulation within the reference range and routine monitoring to decrease premature cardiovascular disease. The management of FCH is similar to other dyslipidemias, which include pharmacologic therapies and lifestyle changes such as diet and exercise.[26]

FDA-approved treatments include HMG-CoA reductase inhibitors (statins), fibric acid derivatives (fibrates), bile acid sequestrants, PCSK9 inhibitors, adenosine triphosphate-citrate lyase inhibitors (bempedoic acid), niacin and ezetimibe.[8][9] Other treatment options include omega-3 fatty acids (fish oil) and MTTP inhibitors (lomitapide).

Statins

• Atorvastatin
• Fluvastatin
• Lovastatin
• Pravastatin
• Rosuvastatin
• Simvastatin
• Pitavastatin[27]

Statins exert their mechanism of action by inhibiting the HMG-CoA reductase enzyme in the hepatocytes, further causing the decreased intracellular synthesis of cholesterol. HMG-CoA reductase is the rate-limiting step in the mevalonate pathway responsible for cholesterol synthesis.[28] The hepatic LDL receptors have a high affinity for LDL and VLDL particles, further causing endocytosis in the liver. Following binding, the cholesterol is mixed with bile salts and excreted as a waste product or recycled, reducing circulating serum cholesterol.

The majority of cholesterol in circulation is produced by internal hepatic synthesis relative to dietary intake, making statins a prevalently used agent in hyperlipidemia and dyslipidemia. The primary therapeutic goal of statins is to lower levels of low-density lipoprotein cholesterol (LDL-C), very-low-density lipoprotein cholesterol (VLDL-C), triglycerides (TG), apolipoprotein B (apo-B) lipoprotein, and total cholesterol, while simultaneously increasing levels of high-density lipoprotein cholesterol (HDL-C).[27]

Fibrates

• Gemfibrozil
• Fenofibrate
• Fenofibric acid[29]

Fibric acids exert mechanistic effects by stimulating peroxisome proliferator-activated alpha (PPAR-a) receptors. Following the binding of the ligand to its target transcriptional factor PPAR-a receptors, it further causes downstream effects and activation of multiple biological processes. The therapeutic action of fibrates is mainly through the beta-oxidation of fatty acids and the metabolism of lipids in circulation, making it effective in hypercholesterolemia and hypertriglyceridemia. This further reduces TG particles and aids in the breakdown of VLDL. This helps decrease the atherosclerotic burden and plaque buildup in coronary vessels from dyslipidemias, further reducing CHD incidence.[29][30]

Bile Acid Sequesterants[31]

• Cholestyramine
• Colestipol
• Colesevelam

Bile acid sequestrants exert their mechanistic effects by decreasing LDL-C absorption in the gastrointestinal tract, further causing its excretion in feces. The sequestrants create an insoluble complex that is not digestible or can be reabsorbed, further depleting bile acids from circulation. The excretion of bile acids initiates more cholesterol in the liver to be converted to bile acids, upregulating LDL receptors in the liver and decreasing plasma LDL-C in circulation.[31]

PCSK9 Inhibitors

• Evolocumab
• Alirocumab
• Inclisiran[32]

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a vital regulator of cholesterol. Mutations in PCSK9 result in a gain of function action, further increasing cholesterol in circulation and etiology for autosomal dominant familial hypercholesterolemia. PCSK9 inhibitors exert their mechanism of action by inhibiting PCSK9 receptors, which reduce LDL-C. The role of PCSK9 is to inhibit LDL receptor recycling which further increases LDL-C in circulation.

Inhibiting the PCSK9 protein halts the inhibitory LDL receptor recycling effect, increasing hepatic LDL receptors, further increasing cholesterol uptake from circulation, and decreasing plasma LDL-C levels. When patients fail to achieve LDL-C targets despite receiving statin and ezetimibe therapy at maximum doses, PCSK9 inhibitors should be considered an additional treatment option.[33][32][34]

Adenosine Triphosphate-citrate Lyase (ACL) Inhibitor

• Bempedoic acid[35]

Bemploic acid exerts its mechanism of action by inhibiting adenosine triphosphate-citrate lyase. The agent is a prodrug that acts in the liver once recognized by the enzyme acyl-CoA-synthetase-1 and converted to its active form, bempedoyl-CoA, further inhibiting ACL. It is FDA approved for heterozygous familial hypercholesterolemia and patients with ASVD who require additional management for decreasing LDL-C.[35]

Others

• Niacin
• Ezetimibe
• Omega-3 fatty acids (fish oil)
• Lomitapide

Differential Diagnosis

Familial combined hyperlipidemia has a broad range of differential diagnoses, as many hereditary and non-genetic etiologies cause increases in serum lipids.[26]

Genetic dyslipidemias include:

• Familial hypercholesterolemia
• Abetalipoproteinemia.
• Hypobetalipoproteinemia.
• Chylomicron retention disease
• Hypertriglyceridemia

FCH may present with more subordinate total serum cholesterol levels and LDL-C than familial hypercholesterolemia.[1] This may be due to the complete expression of FCH transpiring in adulthood. However, the risk of early onset of atherosclerosis is equivalent in both dyslipidemias. Early onset atherosclerosis is multifactorial when considering lipid and non-lipid characteristics such as insulin resistance and inadequate glucose metabolism, fatty liver, HTN, increased uric acid levels, and increased inflammatory markers in circulation.

Prognosis

The prognosis of FCH depends on several factors, including the age of onset, the severity of lipid abnormalities, comorbidities, and treatment adherence. FCH is associated with an increased risk of premature atherosclerotic cardiovascular disease (ASCVD), leading to significant morbidity and mortality if left untreated.

To date, no appropriately designed trials have been conducted to determine the unique risk of cardiovascular disease among patients with familial combined hyperlipidemia. However, some authors propose that their risk may be at least as high as that of patients with heterozygous familial hypercholesterolemia.[36]

Complications

Atherosclerosis

Familial combined hyperlipidemia is linked to a higher likelihood of developing atherosclerosis. While some patients may not experience any symptoms, evaluating the intima-media thickness of the common carotid artery can serve as a means of estimating the risk.[37]

Coronary Artery Disease

A significant association exists between familial combined hyperlipidemia and an elevated coronary artery disease (CAD) risk.[36][38] Notably, males with familial combined hyperlipidemia exhibit a higher prevalence of CAD than females, irrespective of their lipid profiles and other risk factors.[39]

Myocardial Infarction

Familial combined hyperlipidemia ranks high among the common causes of myocardial infarction in young people. In a study by Wiesbauer et al, the prevalence of FCH was 38% among patients younger than 40.[40]

Deterrence and Patient Education

Physicians should explain the genetic basis of FCH and how it is inherited in families. By understanding the genetic basis of the condition, patients can better understand their risk of developing cardiovascular disease and the importance of early intervention. In addition to genetic counseling, patients should be educated on lifestyle modifications that can help manage FCH. This includes proper diet, regular exercise, and weight management. In addition, other modifiable risk factors should be addressed, such as smoking cessation, alcohol consumption, and stress management.

Furthermore, medications may be prescribed to help reduce cholesterol levels and decrease heart disease risk in patients with FCH. It is essential to discuss medication use's potential benefits and risks with their patients and monitor for any adverse effects. Regular follow-up appointments should be scheduled to monitor the patient's progress and adjust the treatment plan. Ongoing support and education help patients manage FCH effectively and maintain their overall health.

Enhancing Healthcare Team Outcomes

FCH is an inherited disorder characterized by abnormal lipid accumulation in the circulation, which can lead to cardiovascular disease and associated complications. Effective management of FCH requires close communication and care coordination among the interprofessional healthcare team, including the primary care clinician, cardiologist, nurse, pharmacist, and mid-level providers.

As part of preventive care, the primary care team should conduct lipid screening to evaluate serum cholesterol levels in accordance with the guidelines provided by the United States Preventive Services Task Force (USPSTF). Additionally, they should assess contributing risk factors for coronary artery disease (CAD) and myocardial infarction, such as hypertension and diabetes. Earlier screening and diagnostic assessments may be warranted in patients at higher risk or with a family history of FCH. Comprehensive patient history should also be obtained, focusing on familial dyslipidemias or family history of heart disease.

The primary care provider should discuss preventative measures and healthy lifestyle strategies with patients, including weight loss, dietary modifications, smoking cessation, alcohol use, and routine exercise. Early goal-directed therapy with first-line statin treatment is recommended for patients with FCH. Patients with uncontrolled hyperlipidemia and underlying comorbidities, such as prior CAD, hypertension, and diabetes, who are at risk for adverse cardiovascular events, may benefit from specialty care provided by cardiologists or endocrinologists for a more comprehensive management plan.[41]

Patient education on FCH is an essential responsibility of the interprofessional team, including primary care providers, specialists, and healthcare professionals such as advanced practice practitioners. This education aims to enhance patient understanding of the disease, improve communication between patients and healthcare providers, and ensure continuity of care, leading to improved outcomes for individuals with genetic dyslipidemia.