Continuing Education Activity

Lipoprotein disorders are clinically important due to the of the role of lipoproteins in atherogenesis and the associated risk of atherosclerotic cardiovascular disease (ASCVD). For patients with known ASCVD (secondary prevention), cholesterol-lowering leads to a consistent reduction in cardiovascular mortality and cardiovascular events in men and women and middle-aged and older patients. Among patients without cardiovascular disease (primary prevention), the data on reduction in atherosclerotic cardiovascular disease events with statin drugs is also well documented. This activity reviews the cause and pathophysiology of hypercholesterolemia and highlights the role of the interprofessional team in its management.

Objectives:

• Recall the risk factors for hypercholesterolemia.
• Describe the evaluation of a patient with hypercholesterolemia.
• Summarize the treatment options for hypercholesterolemia.
• Explore modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by hypercholesterolemia.

Introduction

Lipoprotein disorders are clinically important due to the of the role of lipoproteins in atherogenesis and the associated risk of atherosclerotic cardiovascular disease (ASCVD). For patients with known ASCVD (secondary prevention), cholesterol-lowering leads to a consistent reduction in cardiovascular mortality and cardiovascular events in men and women and middle-aged and older patients. Among patients without cardiovascular disease (primary prevention), the data on reduction in atherosclerotic cardiovascular disease events with statin drugs is also well documented. Patients with triglyceride levels of more than 1000 mg/dl are at increased risk of acute pancreatitis.

Lipoproteins comprise lipids and protein and can be transported in plasma as such, for delivery of cholesterol, triglycerides, and fat-soluble vitamins to the respective organs as needed. In the past, lipoprotein disorders were the domain of specialized lipid physicians. However, the benefit of statin drugs, especially in reducing cardiovascular (CV) events has facilitated the treatment of hypercholesterolemia by family and internal medicine physicians. Despite this paradigm shift, the number of patients who could benefit from lipid-reducing drugs and who are not treated appropriately continues to be a major concern. Hence, the timely evaluation, diagnosis, and treatment of lipoprotein disorders are of primary importance in the practice of medicine. This activity provides a practical approach to hypercholesterolemia and its management. [1][2][3]

Etiology

High cholesterol can be defined as a LDL-cholesterol greater than 190 mg/dL, greater than 160 mg/dL with one major risk factor, or greater than 130 mg/dL with two cardiovascular risk factors. The important risk factors include: 

• Age; male 45 years or older, female 55 years or older
• A positive family history of premature atherosclerotic cardiovascular disease (younger than 55 years in a male and younger than 65yrs in a female)
• Hypertension
• Diabetes
• Smoking
• Low HDL-cholesterol levels (less than 40 mg/dl in male and less than 55 mg/dl in a female).

There are genetic and acquired causes of hypercholesterolemia. The classical genetic disorder is familial hypercholesterolemia due to mutations in the LDL-receptor gene resulting in LDL-C greater than 190 mg/dl in heterozygotes and greater than 450 mg/dl in homozygotes. This defect in the LDL receptor accounts for at least 85% of familial hypercholesterolemia. Familial hypercholesterolemia is caused by loss-of-function mutations in the gene encoding the LDL receptor. The reduction in LDL receptor activity in the liver results in a reduced rate of clearance of LDL from the circulation. The plasma level of LDL increases to a level such that the rate of LDL production equals the rate of LDL clearance by residual LDL receptors as well as non-LDL receptor mechanisms. More than 1600 mutations have been reported in association with familial hypercholesterolemia. The elevated levels of LDL-C in familial hypercholesterolemia are primarily due to a delayed removal of LDL from the blood. Because the removal of IDL is also delayed, the production of LDL from IDL is also increased. Individuals with two mutated LDL receptor alleles (familial hypercholesterolemia homozygotes or compound heterozygotes) have much higher LDL-C levels than those with one mutant allele (familial hypercholesterolemia heterozygotes).[4][5][6]

Other genetic causes of familial hypercholesterolemia include:

• Defective apolipoprotein B (most common with a mutation at position 3500) resulting in a loss of ligand binding to the LDL receptor
• A gain-of-function mutation in proprotein convertase subtilisin/kexin type 9 (PCSK9) gene leading to increased affinity of PCSK9 for the LDL-receptor which results in a more rapid clearance of the LDL-receptor by targeting it to the lysosome for degradation in the liver, thus resulting in high plasma LDL-C.

All of the above genetic causes are transmitted in an autosomal dominant mode. Another rare genetic cause is autosomal recessive hypercholesterolemia, due to a mutation in the LDL receptor adaptor protein resulting in defective endocytosis of the LDL receptors.  However, the commonest cause is polygenic hypercholesterolemia which results from an interaction of unidentified genetic factors compounded by a sedentary lifestyle and an increased intake of saturated and trans-fatty acids. Secondary causes include hypothyroidism, nephrotic syndrome, cholestasis, pregnancy, and certain drugs like cyclosporine, thiazide, and diuretics. These can easily be excluded by history, physical examination, and laboratory tests. It is believed that the elevated LDL particles permeate the vascular intima and get trapped by proteoglycans in the intima. In the intima, LDL is oxidatively modified and promote inflammation and fatty streak formation. Atherogenesis evolves through a fibrous plaque to the mature lesion with plaque rupture culminating in a CV event.

Epidemiology

According to the Center for Disease Control and Prevention (CDC), 73.5 million or 31.7% of adults in the United States have high levels of LDL-C and are at twice the risk for heart disease than people with normal levels. Only 48.1% are receiving treatment to lower LDL-C levels. Recent data suggests that the classic disorder, familial hypercholesterolemia has a prevalence of estimate of 1/300,000 as homozygous and 1/250 as a heterozygote. In certain populations such as the French Canadians, Lebanese, and Afrikaners it could be as high as 1/100.[7][8][9]

In the US, the highest level of LDL cholesterol occurs in Hispanic males, followed by African Americans and white males. Overall, elevated LDL-C is more common in females than in males.

Pathophysiology

In familial hypercholesterolemia, there is either a problem with the LDL receptor or it is missing. Without the receptor, uptake of cholesterol into the liver is not possible. The liver usually processes two-thirds of the circulating LDL. Hundreds of mutations of the LDL receptor have been identified, which express themselves as hypercholesterolemia.

History and Physical

Both history and physical examination can yield useful information. If there is a positive family history of premature atherosclerotic cardiovascular disease, constructing a family tree is useful. Also asking about secondary causes such as smoking, diabetes, dietary intake of total calories, saturated, and trans fats, physical activity, drug therapies, and symptoms of CV disease (angina pectoris, intermittent claudication, transient ischemic attacks) is also important. On physical examination look for features of hypothyroidism (bradycardia, dry skin, delayed reflexes) Nephrotic syndrome (edema, ascites), cholestasis (jaundice, hepatomegaly).

In patients with hypercholesterolemia, palpitate all pulses and elicit carotids and femoral bruits. Also, carefully examine the tendon xanthoma (Achilles tendon and extensor tendons on the dorsum of the hand), xanthelasma, and arcus senilis if the patient is younger than 50 years old. In suspected familial hypercholesterolemia patients, a careful examination of the heart for supra-valvar aortic stenosis due to atheroma deposition is warranted.

Evaluation

A plasma lipid profile should be measured in all adults older than 40 years, preferably after a 10 to 12-hour overnight fast. The lipid profile reports the total cholesterol, triglycerides, and HDL-cholesterol, and calculates the LDL-cholesterol by the Friedewald Equation:

• LDL-C = Total Cholesterol – VLDL(TG/5) – HDL-C

This formula (the Friedewald formula) is accurate if test results are obtained on fasting plasma and if the triglyceride level does not exceed 200 mg/dL. By convention, it cannot be used if the triglyceride level is greater than 400 mg/dL since high triglycerides alter the TG/5 or VLDL-C. Many methods can directly measure LDL-C. Secondary causes can be excluded by doing the following tests: TSH (hypothyroidism), glucose (diabetes), urinalysis and serum albumin (nephrotic syndrome), and bilirubin and alkaline phosphatase (cholestasis). Ideally, if there is an abnormal lipid profile (high cholesterol), the test should be repeated within 2 weeks to confirm the diagnosis before embarking on lifelong therapy.[10][11][12]

Screening recommendations:

• Men older than 35
• Women older than 45
• Presence of diabetes
• Tobacco use
• Family history of cardiac disease
• Personal history of heart disease or peripheral vascular disease
• Obesity (BMI > 30)
• Hypertension

Treatment / Management

The cornerstone of treatment of hypercholesterolemia is a healthy lifestyle, an optimum weight, no smoking, exercising for 150 minutes per week, and a diet low in saturated and trans-fatty acids and enriched in fiber, fruit, and vegetables and fatty fish. Plant stanols at a dose of 2 g/d can help reduce LDL-C levels. The drug class of choice is the statin which can lower LDL-C from 22% to 50%. Also, they have been shown to reduce cardiovascular events in both primary and secondary prevention trials. The major side effects are elevated transaminases, myalgia, and myopathy and new-onset diabetes. If transaminases exceed three times the upper limit of normal, the statin dose should be reduced, or a lower dose of another statin should be used. Myopathy is a serious problem since it can result in rhabdomyolysis and acute renal failure. Certain drugs in combination with statins increase this risk. These include gemfibrozil, macrolide antibiotics azole antifungals, protease inhibitors, cyclosporine, nefazodone, and other CYP3A4 inhibitors, and multisystem diseases. However, some patients cannot achieve adequate control of their LDL-C levels even with high-dose statin therapy and require additional drugs.

Cholesterol absorption inhibitors (ezetimibe) and/or bile acid sequestrants are the next-line of drugs given their safety in combination with statins. Niacin in combination with the above can be used to further lower LDL-C in primary prevention but not in patients with atherosclerotic cardiovascular disease. Currently, heterozygous FH patients whose LDL-C levels remain markedly elevated (more than 200 mg/dL with cardiovascular disease or more than 300 mg/dL without CVD) on maximally tolerated drug therapy are candidates for LDL apheresis. This is a physical method of purging the blood of LDL in which the LDL particles are removed selectively from the circulation. Usually, LDL apheresis is performed every 2 weeks. A new class of drugs, PCSK9 inhibitors (monoclonal antibodies), can lower LDL-C up to 60% on statin therapy and are approved for use in FH and patients on statin therapy not at their goal.

Treatment of heterozygotes with HMG-CoA reductase inhibitors may normalize LDL levels. However, achieving optimal levels may require one of the combinations involving reductase inhibitors, niacin, bile acid sequestrants, and ezetimibe. Levels of LDL cholesterol less than 100 mg/dL can be obtained with combinations of these drugs in some patients. Treatment of individuals with homozygosity or combined heterozygosity is challenging. Partial control may be achieved with medications including antisense oligonucleotide directed at Apo B-100 synthesis, inhibition of microsomal triglyceride transfer protein, and ezetimibe. Statins and monoclonal antibodies directed at proprotein convertase subtilisin/kexin type 9 (PCSK9) protein are useful if some residual receptor activity is present and there is no null mutation. LDL apheresis in conjunction with medications can be very effective. Striking reduction of LDL levels is observed after liver transplantation, illustrating the important role of hepatic receptors in LDL metabolism.

In conclusion, hypercholesterolemia is a mammoth problem facing us, and it behooves us as health care professionals to get more patients on efficacious therapies like statins which are cost-effective since they are now largely generic. The optimum LDL-C for the population is less than 100mg/dL. In patients with atherosclerotic cardiovascular disease, the goal should be less than 70 mg/dl or a 50% reduction in LDL-C. For others, the goal should be an LDL-C less than 100 mg/dl or a 30% to 50% reduction in LDL-C.[13][14][15]

Differential Diagnosis

• Smoking
• Hypothyroidism
• Diabetes mellitus
• Nephrotic syndrome
• Alcoholism

Prognosis

The biggest risk of hypercholesterolemia is adverse cardiac events. However, since the introduction of the statins, the mortality associated with hypercholesterolemia has significantly decreased in many trials. Today, cholesterol-lowering is a useful strategy for the primary prevention of heart disease.

Complications

• Heart Disease
• Stroke
• Peripheral vascular disease

Postoperative and Rehabilitation Care

Dietary guidelines

• Total fat should make up less than 30% of energy intake
• Saturate fats should make up less than 7% of total calories
• Carbohydrates should make up 60% of the total calories

Exercise may not lower LCL-C but aerobic exercise may improve insulin sensitivity, lower triglyceride levels and increase HDL.

Enhancing Healthcare Team Outcomes

Hypercholesterolemia is common and associated with enormous morbidity and mortality, leading to high healthcare costs. To manage the condition, an interprofessional team dedicated to the prevention of heart disease is essential. Besides physicians, the role of the pharmacist, nurse, dietitian, and physical therapist are critical in the management of hypercholesterolemia.

The nurse is an ideal position to educate the patient about changes in lifestyle, eating a healthy diet and resuming an active lifestyle. The pharmacist should ensure compliance with the statin medications and offer antismoking aids. Further, the pharmacist should also be aware of the side effects of statins like muscle pain and liver damage; and ensure that regular blood work is performed.

The dietitian should educate the patient on dietary modifications and avoidance of fatty foods.

The patient should enroll in an exercise program and achieve healthy body weight. Patients who fail to lower cholesterol with the above measures should be referred to a bariatric surgeon. In some patients with low self-esteem and morale, a mental health nurse should offer counseling. Members of the interprofessional team should communicate with each other so that all patients are provided with the acceptable standard of care treatment.  [16][17][18] (level V)

Outcomes

With the availability of the statins, the adverse effects of hypercholesterolemia have been decreased. More importantly, if the lifestyle is altered, then there is a significant improvement in body weight, hypertension, and diabetes. Cessation of smoking is also very important in improving outcomes. Countless studies have shown that when hypercholesterolemia is appropriately managed, the outcomes are good. [7][19](Level II)