Hypercholesterolemia

Etiology

High cholesterol can be defined as a LDL-cholesterol greater than 190 mg/dL, greater than 160 mg/dL with 1 major risk factor, or greater than 130 mg/dL with 2 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 65 years in a female)
• Hypertension
• Diabetes
• Smoking
• Low HDL-cholesterol levels (less than 40 mg/dl in males and less than 55 mg/dl in females).

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 levels 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. A reduction in LDL receptor activity in the liver results in a slower clearance of LDL from the circulation. The plasma LDL level increases to a level at which the rate of LDL production equals the rate of LDL clearance by residual LDL receptors and non-LDL receptor mechanisms. More than 1600 mutations have been reported in association with familial hypercholesterolemia. The elevated LDL-C levels in familial hypercholesterolemia are primarily due to delayed LDL clearance from the blood. Because the removal of IDL is delayed, LDL production from IDL is increased. Individuals with 2 mutated LDL receptor alleles (familial hypercholesterolemia homozygotes or compound heterozygotes) have much higher LDL-C levels than those with 1 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 the 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 manner. Another rare genetic cause is autosomal recessive hypercholesterolemia, due to a mutation in the LDL receptor adaptor protein, which results in defective endocytosis of LDL receptors. However, the most common cause is polygenic hypercholesterolemia, which results from the interaction of unidentified genetic factors, compounded by a sedentary lifestyle and increased intake of saturated and trans-fatty acids. Secondary causes include hypothyroidism, nephrotic syndrome, cholestasis, pregnancy, and certain drugs like cyclosporine, thiazides, and diuretics. These can easily be excluded by history, physical examination, and laboratory tests. It is believed that elevated LDL particles permeate the vascular intima and are trapped by proteoglycans within it. In the intima, LDL is oxidatively modified, promoting inflammation and fatty streak formation. Atherosclerosis evolves from a fibrous plaque to a mature lesion, with plaque rupture culminating in a cardiovascular event.

Epidemiology

According to the Centers 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, cholesterol cannot be taken up by the liver. The liver usually processes two-thirds of the circulating LDL. Hundreds of mutations in the LDL receptor have been identified, which result in hypercholesterolemia. Please see Familial Hypercholesterolemia for additional information.

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 cardiovascular 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), and 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 performing the following tests: TSH (hypothyroidism), glucose (diabetes), urinalysis, serum albumin (nephrotic syndrome), and bilirubin and alkaline phosphatase (cholestasis). Ideally, if there is an abnormal lipid profile (eg, high cholesterol), the test should be repeated within 2 weeks to confirm the diagnosis before initiating 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 the treatment of hypercholesterolemia is a healthy lifestyle, an optimal weight, no smoking, exercising for 150 minutes per week, and a diet low in saturated and trans-fatty acids and enriched in fiber, fruit, 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%. They have also been shown to reduce cardiovascular events in both primary and secondary prevention trials. The major side effects are elevated transaminases, myalgia, myopathy, and new-onset diabetes. If transaminases exceed 3 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 drugs, given their safety when combined with statins. Niacin, when combined with the above, can 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 removing LDL from the blood, in which LDL particles are selectively removed from the circulation. Usually, LDL apheresis is performed every 2 weeks. A new class of drugs, PCSK9 inhibitors (monoclonal antibodies), can lower LDL-C by up to 60% on statin therapy and are approved for use in FH and in patients on statin therapy who are not at their goal.

Treatment of heterozygotes with HMG-CoA reductase inhibitors may normalize LDL levels. However, achieving optimal levels may require 1 of the combinations involving reductase inhibitors, niacin, bile acid sequestrants, and ezetimibe. Levels of LDL cholesterol below 100 mg/dL can be achieved 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 oligonucleotides directed against ApoB-100 synthesis, inhibitors 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. A striking reduction in 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 level below 100 mg/dL or a 30% to 50% reduction in LDL-C.[13][14][15](B3)

Differential Diagnosis

Differential diagnosis for hypercholesterolemia includes:

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

Prognosis

The biggest risk of hypercholesterolemia is adverse cardiac events. However, since the introduction of 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

Complications with hypercholesterolemia include:

• Heart Disease
• Stroke
• Peripheral vascular disease