Polygenic Hypercholesterolemia

Etiology

Polygenic hypercholesterolemia, caused by a combination of genetic and environmental factors, is attributed to multiple inherited variations in small-effect alleles of single-nucleotide polymorphisms (SNPs) rather than a single large-effect gene mutation.[5] Researchers have identified over 50 genomic loci associated with elevated LDL-C levels.[1] Each of these SNPs exerts a minor effect on cholesterol synthesis, metabolism, and clearance, collectively leading to increased LDL cholesterol levels. In addition to genetic factors, lifestyle-related risk factors (poor diet, physical inactivity, obesity, and other lifestyle choices) are believed to contribute to elevated cholesterol levels and play a role in the development of polygenic hypercholesterolemia.[6]

Epidemiology

More than 100 million people in the United States (53% of the population) have elevated LDL-C levels. Only 50% of these individuals receive treatment, and <35% achieve adequate control of their blood cholesterol levels, putting them at an increased risk for ASCVD.[7] Asian Indians, Filipinos, Japanese individuals, and Vietnamese individuals have a higher prevalence of elevated LDL-C levels compared to White individuals.[8]

Recent studies suggest that the prevalence of heterozygous familial hypercholesterolemia may be close to 1 in 250 individuals, corresponding to approximately 30 million affected individuals worldwide.[9] Unfortunately, it is estimated that fewer than 10% of familial hypercholesterolemia cases have been correctly identified.[10] Approximately 20% to 30% of patients diagnosed with clinical familial hypercholesterolemia are believed to have polygenic hypercholesterolemia.[11]

Pathophysiology

Hypercholesteremia involves the interplay between susceptible genotypes and provoking environmental factors.[12] Familial hypercholesterolemia is an autosomal dominant inherited disease that occurs when there is a mutation in the LDL-R, APOB100, or PCSK9 genes.[13] However, these genes are typically identified in only about 40% of patients diagnosed with familial hypercholesterolemia.[2] Patients exhibiting a phenotypic expression of familial hypercholesterolemia without identifiable mutations are believed to have polygenic inheritance.[14] Patients with variant negative familial hypercholesterolemia may be referred to as "pseudo-familial hypercholesterolemia” or “polygenic familial hypercholesterolemia” patients.[13] In such cases, instead of a single large gene mutation, there is an accumulation of polymorphisms in multiple genes, small-effect LDL-C raising alleles, leading to the development of polygenic familial hypercholesterolemia.[15] The Global Lipid Genetic Consortium has identified approximately 95 loci that influence LDL-C levels, contributing to variations in lipid traits and playing a role in the development of extreme lipid phenotypes.

History and Physical

Polygenic hypercholesterolemia is asymptomatic and is often detected only during routine screening. When obtaining the patient's history, healthcare professionals should inquire about family members who had sudden premature cardiac death or premature ASCVD.[16] Premature disease is defined as a diagnosis of coronary artery disease (CAD) in males 55 or younger and females 65 or younger. In addition, assessing the family history of patients with hypercholesterolemia and early CAD in first-degree relatives is essential. Healthcare providers should also evaluate lifestyle factors, such as tobacco use, diet, and physical activity levels, that may contribute to elevated cholesterol levels and cardiovascular risk. 

During physical examination, assessing for the presence of corneal arcus is crucial, which manifests as a gray-white ring-like deposit surrounding the cornea. This finding is highly specific in younger patients but is not very sensitive.[1] Another physical exam finding to look for is tendon or tuberous xanthomas, particularly in the finger extensor tendons or the Achilles tendon. Sonographic evaluation of the Achilles tendon can further enhance the detection of xanthomas.[16]

Evaluation

The screening for dyslipidemias in adults is a controversial topic that lacks consensus. Nevertheless, identifying dyslipidemias in younger adults is important, as it has the potential to enable early intervention and further help to decrease the patient's lifetime ASCVD risk. Certain guidelines recommend against universal screening for individuals younger than 40 who lack risk factors. On the other hand, other guidelines, such as the US National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), recommend that all adults begin screening at 20 and subsequently repeat every 5 years thereafter.[17] The best initial screening laboratory study would be either a standard fasting or non-fasting lipid profile, which includes triglycerides, LDL-C, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and non-HDL-C.

There is no agreement on which alleles and loci should be included in genetic risk scores for polygenic hypercholesterolemia. In addition, whether individual effects should be weighted remains unclear.[5] However, screening family members is important, as the LDL-C-raising alleles in polygenic hypercholesterolemia are known to cluster within families. 

Before diagnosing familial hypercholesterolemia or polygenic hypercholesterolemia, healthcare providers must first evaluate patients for secondary causes of hypercholesterolemia, which may include nephrotic syndrome, hypothyroidism, or liver disease.[1]

Treatment / Management

Patients with genetic disorders causing hypercholesterolemia face a high risk of developing CVD, and the treatment is crucial. Treatment approaches include aggressive lipid lowering, involving dietary and lifestyle modifications, medications, and, in some cases, invasive treatments such as apheresis.[1] These treatment strategies have been shown to reduce cardiovascular events and also decrease visibly apparent CAD on angiography. Treating genetic disorders that cause hypercholesterolemia requires lifelong management and regular follow-up, as there are currently no curative treatments available.[18]

All patients should receive counseling on smoking cessation, regular exercise, and weight management. Addressing underlying metabolic conditions that may contribute to the condition, such as diabetes mellitus and hypertension, is crucial.[19] Following a diet low in saturated fats may reduce LDL levels by 8% to 10%, whereas limiting cholesterol consumption to <200 mg daily may lead to a reduction of LDL levels by 3% to 5%.[18] Unfortunately, strict adherence to a healthy lifestyle is seldom enough to lower LDL-C levels, and drug therapy is frequently required.[1] 

Medications should be initiated for all patients with LDL-C levels exceeding 190 mg/dL. The primary objective initially is to achieve a minimum 50% reduction through statin therapy, which remains the first step in pharmacologic treatment. If this goal is not attained, guidelines suggest aiming for an LDL-C target of <100 mg/dL and considering non-statin drug treatments. 

High-intensity statins, such as atorvastatin at a daily dose of 40 to 80 mg or rosuvastatin at 20-40 mg daily, are the preferred initial treatment.[20] These drugs are hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors with well-studied benefits on morbidity and mortality associated with CVD.

Ezetimibe, which selectively blocks cholesterol absorption, should be introduced if the LDL-C target is not reached.[18] Adding ezetimibe at a daily dose of 10 mg in conjunction with statin therapy provides an additional approximately 23% reduction in LDL-C levels, or 18%, when used as a monotherapy.[20] The Improved Reduction of Outcomes: The Vytorin Efficacy International (IMPROVE-IT) trial showed that the combination of ezetimibe and statins could further reduce LDL-C levels in the blood.[14]

If LDL-C levels remain above the target, PCSK9 inhibitors such as evolocumab and alirocumab can be incorporated, resulting in an additional 50% to 60% decrease in LDL-C levels.

These are monoclonal antibodies administered subcutaneously to decrease LDL and lipoprotein levels (a).[21](B3)

Bempedoic acid could also be considered as an additional treatment option. Bempedoic acid is an adenosine triphosphate citrate lyase inhibitor, a key enzyme required in cholesterol biosynthesis. In patients who are already receiving statin therapy, adding 180 mg of bempedoic acid daily decreased LDL-C levels by an additional 17%.[21](B3)

Inclisiran is a small interfering RNA that reduces LDL-C levels by inhibiting the translation of PCSK9. When administered subcutaneously every 6 months, except for the first 2 dosages given 3 months apart, inclisiran can achieve over 50% reduction in LDL-C levels with each 6-month dosing interval.[14] 

In addition, lipoprotein apheresis can be used in patients with a high risk of CVD who are not able to achieve target LDL-C levels with medications. When provided every 1 to 2 weeks, this treatment can reduce LDL-C levels by 50% to 75%.[14]

Differential Diagnosis

Numerous factors are recognized for their role in elevating LDL-C concentration. Before diagnosing polygenic hypercholesterolemia, it is imperative to exclude secondary causes of hypercholesterolemia. Differential diagnoses include conditions such as diabetes mellitus, excessive alcohol intake, hypothyroidism, nephrotic syndrome, chronic kidney disease, anorexia, metabolic syndrome, and obesity.[3] Certain medications, including glucocorticoids, diuretics, and cyclosporine, may increase LDL-C levels.[7] Within the realm of hereditary causes, familial hypercholesterolemia, familial combined hyperlipidemia, and dysbetalipoproteinemia warrant significant consideration.[22]

Prognosis

Patients with a higher LDL-C burden have a consequential higher atherosclerotic burden. This is more common in patients with monogenic hypercholesterolemia than in those with polygenic hypercholesterolemia. Patients with polygenic hypercholesterolemia can be managed in general practice, whereas patients with monogenic hypercholesterolemia may require management by a lipid specialist. Patients with polygenic hypercholesterolemia have 50% fewer "affected" relatives than those with a monogenic cause, so they do not require cascade testing.[3]

Multiple treatment options can be used independently or in conjunction to reduce LDL-C levels. The introduction of statin therapy has resulted in a reduction of coronary mortality by more than one-third in patients with familial hypercholesterolemia. Patients with familial hypercholesterolemia without known coronary heart disease (CHD) who have been treated have no greater CHD rate compared to the general population. Studies have shown that men have had a more significant reduction in CHD over the past 20 years compared to women, which may be due to differences in high-intensity statin initiation.[3]

Complications

Individuals with hyperlipidemia are at twice the risk of developing CVD compared to those with normal total cholesterol levels. In the case of polygenic hypercholesterolemia, the risk of developing CHD at a younger age is even greater compared to the general population.[7] Such individuals are more predisposed to experiencing conditions such as myocardial infarction, peripheral limb ischemia, or stroke.[17]